Trpv1 antagonists

ABSTRACT

The present invention relates to compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein X, R 1 , R 2 , R 3 , R 4 , R 5 , m, and n are defined in the specification are TRPV1 antagonists. Compositions comprising such compounds and methods for treating conditions and disorders using such compounds and compositions are also disclosed.

This application claims priority to U.S. Ser. No. 60/982,200, filed Oct.24, 2007 and is incorporated herein by reference.

TECHNICAL FIELD

The present invention generally relates to cycloalkene containingcompounds, compositions comprising such compounds, and methods oftreating conditions and disorders using such compounds and compositions.

BACKGROUND

Nociceptors are primary sensory afferent (C and Aδ fibers) neurons thatare activated by a wide variety of noxious stimuli including chemical,mechanical, thermal, and proton (pH<6) modalities. The lipophillicvanilloid, capsaicin, activates primary sensory fibers via a specificcell surface capsaicin receptor, cloned as the transient receptorpotential vanilloid-1 (TRPV 1). TRPV1 is also known as vanilloidreceptor-1 (VR1). The intradermal administration of capsaicin ischaracterized by an initial burning or hot sensation followed by aprolonged period of analgesia. The analgesic component of the TRPV1receptor activation is thought to be mediated by a capsaicin-induceddesensitization of the primary sensory afferent terminal. Thus, the longlasting anti-nociceptive effect of capsaicin has prompted the clinicaluse of capsaicin analogs as analgesic agents. Further, capsazepine, acapsaicin receptor antagonist can reduce inflammation-inducedhyperalgesia in animal models. TRPV1 receptors are also localized onsensory afferents, which innervate the bladder. Capsaicin orresiniferatoxin has been shown to ameliorate incontinence symptoms uponinjection into the bladder.

The TRPV1 receptor has been called a “polymodal detector” of noxiousstimuli since it can be activated in several ways. The receptor channelis activated by capsaicin and other vanilloids, and thus is classifiedas a ligand-gated ion channel. The TRPV1 receptor activation bycapsaicin can be blocked by the competitive TRPV1 receptor antagonist,capsazepine. The channel can also be activated by protons. Under mildlyacidic conditions (pH 6-7), the affinity of capsaicin for the receptoris increased, whereas at pH<6, direct activation of the channel occurs.In addition, when membrane temperature reaches 43° C., the channel isopened. Thus heat can directly gate the channel in the absence ofligand. The capsaicin analog, capsazepine, which is a competitiveantagonist of capsaicin, blocks activation of the channel in response tocapsaicin, acid, or heat.

The channel is a nonspecific cation conductor. Both extracellular sodiumand calcium enter through the channel pore, resulting in cell membranedepolarization. This depolarization increases neuronal excitability,leading to action potential firing and transmission of a noxious nerveimpulse to the spinal cord. In addition, depolarization of theperipheral terminal can lead to release of inflammatory peptides suchas, but not limited to, substance P and CGRP, leading to enhancedperipheral sensitization of tissue.

Recently, two groups have reported the generation of a “knock-out” mouselacking the TRPV1 receptor. Electrophysiological studies of sensoryneurons (dorsal root ganglia) from these animals revealed a markedabsence of responses evoked by noxious stimuli including capsaicin,heat, and reduced pH. These animals did not display any overt signs ofbehavioral impairment and showed no differences in responses to acutenon-noxious thermal and mechanical stimulation relative to wild-typemice. The TRPV1 (−/−) mice also did not show reduced sensitivity tonerve injury-induced mechanical or thermal nociception. However, theTRPV1 knock-out mice were insensitive to the noxious effects ofintradermal capsaicin, exposure to intense heat (50-55° C.), and failedto develop thermal hyperalgesia following the intradermal administrationof carrageenan.

We herein describe a novel series of TRPV1 antagonists.

SUMMARY

The present invention generally provides cycloalkenes containingcompounds and pharmaceutical compositions and methods for the treatmentof disorders using these compounds and pharmaceutical compositions.

One aspect of the invention is directed towards compounds of formula(I), or pharmaceutically acceptable salts, prodrugs, salts of prodrugs,or combinations thereof,

wherein

R¹ is phenyl or a monocyclic heteroaryl, each of which is optionallysubstituted with 1, 2, 3, 4, or 5 substituents as represented by R⁶groups;

R² is halogen, alkyl, haloalkyl, —CN, —O(alkyl), —O(haloalkyl), —OH,—NH₂, —N(H)(alkyl), or —N(alkyl)₂; or

R² and the adjacent carbon atom, together with the carbon atom to whichR² is attached, form a 3-6 membered monocyclic cycloalkyl ring that isoptionally substituted with 1, 2, 3, or 4 substituents independentlyselected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl,haloalkoxyalkyl, haloalkyl, arylalkyl, aryl, aminoalkyl, amino, andhalogen, wherein the aryl and the aryl moiety of the arylalkyl are eachindependently unsubstituted or substituted with 1, 2, 3, 4, or 5substituents selected from the group consisting of alkyl, alkenyl,alkynyl, halogen, OH, O(alkyl), O(haloalkyl), amino, and haloalkyl;

R³ is hydrogen or C₁₋₆ alkyl;

R⁴ is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle,wherein each R⁴ is optionally substituted with 1, 2, 3, 4, 5, or 6substituents as represented by R⁷ groups;

R⁵ represents an optional substituent on the cycloalkene ring, and ishaloalkyl, halogen, —OH, —NO₂, NH₂, N(H)(alkyl), N(alkyl)₂, alkyl,alkenyl, alkynyl, or -G¹;

X is O, S, or N(R^(z)) wherein R^(z) is hydrogen, alkyl, or CN;

m is 0, 1, or 2;

n is 0 or 1;

R⁷, at each occurrence, is independently alkyl, alkenyl, alkynyl, oxo,—NO₂, —CN, halogen, -G², —OR^(a), —OC(O)R^(a), —SR^(a), —SF₅,—S(O)R^(b), —S(O)₂R^(b), —S(O)₂N(R^(a))(R^(c)), —N(R^(a))(R^(c)),—N(R^(c)C)C(O)R^(a), —N(R^(c))S(O)₂R^(b), —N(R^(c))C(O)N(R^(a))(R^(c)),—N(R^(c))S(O)₂N(R^(a))(R^(c)), —C(O)R^(a), —C(O)O(R^(a)),—C(O)N(R^(a))(R^(c)), haloalkyl, —(CR^(j)R^(k))_(p)—CN,—(CR^(j)R^(k))_(p)—OR^(a), (CR^(j)R^(k))_(p)—OC(O)R^(a),(CR^(j)R^(k))_(p)—SR^(a), (CR^(j)R^(k))_(p)—S(O)R^(b),—(CR^(j)R^(k))_(p)—S(O)₂R^(b), —(CR^(j)R^(k))_(p)—N(R^(a))(R^(c)),—(CR^(j)R^(k))_(p)—N(R^(c))C(O)R^(a),—(CR^(j)R^(k))_(p)—N(R^(c))S(O)₂R^(b),—(CR^(j)R^(k))_(p)—N(R^(c))C(O)N(R^(a))(R^(c)),(CR^(j)R^(k))_(p)—N(R^(c))S(O)₂N(R^(a))(R^(c)),—(CR^(j)R^(k))_(p)—C(O)R^(a), —(CR^(j)R^(k))_(p)—C(O)O(R^(a)),—(CR^(j)R^(k))_(p)—C(O)N(R^(a))(R^(c)), or —(CR^(j)R^(k))_(p)-G²;

R^(a), at each occurrence, is independently hydrogen, alkyl, haloalkyl,-G², or —(CR^(u)R^(v))_(w)-G²;

R^(b), at each occurrence, is independently alkyl, haloalkyl, -G², or—(CR^(u)R^(v))_(w)-G²;

G¹ and G², are each independently aryl, heteroaryl, cycloalkyl,cycloalkenyl, or heterocycle; each of which is independentlyunsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents asrepresented by R⁸ groups;

R⁶, at each occurrence, is independently alkyl, alkenyl, alkynyl, —NO₂,—CN, halogen, —OR^(d), —OC(O)R^(d), —SR^(d), —S(O)R^(e), —S(O)₂R^(d),—S(O)₂N(R^(d))(R^(f)), —N(R^(d))(R^(f)), —N(R^(f))C(O)R^(d),—N(R^(f))S(O)₂R^(e), —N(R^(f))C(O)N(R^(d))(R^(f)),—N(R^(f))S(O)₂N(R^(d))(R^(f)), —C(O)R^(d), —C(O)O(R^(d)),—C(O)N(R^(d))(R^(f)), haloalkyl, —(CR^(s)R^(t))_(q)—CN,—(CR^(s)R^(t))_(q)—OR^(a), —(CR^(s)R^(t))_(q)—SR^(d),—(CR^(s)R^(t))_(q)—S(O)R^(e), —(CR^(s)R^(t))_(q)—S(O)₂R^(e),—(CR^(s)R^(t))_(q)—N(R^(d))(R^(f)), (CR^(s)R^(t))_(q)—N(R^(f))C(O)R^(d),—(CR^(s)R^(t))_(q)—N(R^(f))S(O)₂R^(e),—(CR^(s)R^(t))_(q)—N(R^(f))C(O)N(R^(d))(R^(f)),—(CR^(s)R^(t))_(q)—N(R^(f))S(O)₂N(R^(d))(R^(f)),—(CR^(s)R^(t))_(q)—C(O)R^(d), —(CR^(s)R^(t))_(q)—C(O)O(R^(d)), or—(CR^(s)R^(t))_(q)—C(O)N(R^(d))(R^(f));

R⁸, at each occurrence, is independently alkyl, alkenyl, alkynyl, oxo,—NO₂, —CN, halogen, —OR^(d), —OC(O)R^(d), —SR^(d), —S(O)R^(e),—S(O)₂R^(e), —S(O)₂N(R^(d))(R^(f)), —N(R^(d))(R^(f)),—N(R^(f))C(O)R^(d), —N(R^(f))S(O)₂R^(e), —N(R^(f))C(O)N(R^(d))(R^(f)),—N(R^(f))S(O)₂N(R^(d))(R^(f)), —C(O)R^(d), —C(O)O(R^(d)),—C(O)N(R^(d))(R^(f)), haloalkyl, —(CR^(s)R^(t))_(q)—CN,—(CR^(s)R^(t))_(q)—OR^(a), —(CR^(s)R^(t))_(q)—OC(O)R^(d),—(CR^(s)R^(t))_(q)—SR^(d), (CR^(s)R^(t))_(q)—S(O)R^(e),—(CR^(s)R^(t))_(q)—S(O)₂R^(e), —(CR^(s)R^(t))_(q)—N(R^(d))(R^(f)),—(CR^(s)R^(t))_(q)—N(R^(f))C(O)R^(d),—(CR^(s)R^(t))_(q)—N(R^(f))S(O)₂R^(e),—(CR^(s)R^(t))_(q)—N(R^(f))C(O)N(R^(d))(R^(f)),—(CR^(s)R^(t))_(q)—N(R^(f))S(O)₂N(R^(d))(R^(f)),—(CR^(s)R^(t))_(q)—C(O)R^(d), —(CR^(s)R^(t))_(q)—C(O)O(R^(d)), or—(CR^(s)R^(t))_(q)—C(O)N(R^(d))(R^(f));

R^(c), R^(d) and R^(f), at each occurrence, are each independentlyhydrogen, alkyl, or haloalkyl;

R^(e), at each occurrence, is independently alkyl or haloalkyl;

R^(j), R^(k), R^(s), R^(t), R^(u), and R^(v), at each occurrence, areeach independently hydrogen, halogen, alkyl, or haloalkyl; and

p, q, and w, at each occurrence, are each independently 1, 2, 3, or 4.

Another aspect of the inventions relates to a pharmaceutical compositioncomprising one or more compounds of the invention or a pharmaceuticallyacceptable salt or solvate thereof, and one or more pharmaceuticallyacceptable carriers, alone or co-administered with acetaminophen, orwith one or more nonsteroidal anti-inflammatory drug (NSAID), or acombination thereof.

Yet other aspect provides methods for treating diseases or disorders asdefined herein below. Said methods comprise the step of administeringtherapeutically effective amount of one or more of the compound of theinvention, or a pharmaceutically acceptable salt or solvate thereof, toa subject in need thereof, optionally with one or more pharmaceuticallyacceptable carrier, and alone or in combination with one or morenonsteroidal anti-inflammatory drug (SAID), or with acetaminophen, or acombination thereof.

Further aspect of the invention provides the use of a compound of theinvention, or a pharmaceutically acceptable salt or solvate thereof, inthe manufacture of a medicament for the treatment of disease ordisorders as defined herein below, alone or in combination withacetaminophen, or with one or more nonsteroidal anti-inflammatory drug(NSAID), or with a combination of acetaminophen and NSAID; and alone orin combination with one or more pharmaceutically acceptable saltthereof.

It is to be understood that both the foregoing general description andthe following detailed description are exemplary, but are notrestrictive, of the invention.

DETAILED DESCRIPTION

Compounds of formula (I) are disclosed in this invention,

wherein R¹, R², R³, R⁴, R⁵, X, m, and n are defined above in the Summaryof the Invention and below in the Detailed Description. Compositionscomprising such compounds and methods for treating conditions anddisorders using such compounds and compositions are also disclosed.

In various embodiments, the present invention provides at least onevariable that occurs more than one time in any substituent or in thecompound of the invention or any other formulae herein. Definition of avariable on each occurrence is independent of its definition at anotheroccurrence. Further, combinations of substituents are permissible onlyif such combinations result in stable compounds. Stable compounds arecompounds, which can be isolated from a reaction mixture.

a. DEFINITION

As used in the specification and the appended claims, unless specifiedto the contrary, the following terms have the meaning indicated:

The term “alkenyl” as used herein, means a straight or branched chainhydrocarbon containing from 2 to 10 carbons and containing at least onecarbon-carbon double bond. Representative examples of alkenyl include,but are not limited to, ethenyl, 2-propenyl, 2-methyl-2-propenyl,3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, and3-decenyl.

The term “alkyl” as used herein, means a saturated, straight or branchedhydrocarbon chain containing from 1 to 10 carbon atoms. The term “C₁₋₆alkyl” as used herein, means a saturated, straight or branchedhydrocarbon chain containing from 1 to 6 carbon atoms. The term “C₁₋₃alkyl” as used herein, means a saturated, straight or branchedhydrocarbon chain containing from 1 to 3 carbon atoms. Representativeexamples of alkyl include, but are not limited to, methyl, ethyl,n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl,n-pentyl, isopentyl, neopentyl, n-hexyl, 1-methylbutyl, 2-methylbutyl,3-methylbutyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl,2,2-dimethylpropyl, 1-methylpropyl, 1-ethylpropyl,1,2,2-trimethylpropyl, 3-methylhexyl, 2,2-dimethylpentyl,2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

The term “alkoxy” as used herein, means an alkyl group, as definedherein, appended to the parent molecular moiety through an oxygen atom.Representative examples of alkoxy include, but are not limited to,methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, andhexyloxy.

The term “alkoxyalkyl” as used herein, means an alkoxy group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of alkoxyalkyl include, butare not limited to, tert-butoxymethyl, 2-ethoxyethyl, 2-methoxyethyl,and methoxymethyl.

The term “alkylene” means a divalent group derived from a saturated,straight or branched chain hydrocarbon of from 1 to 10 carbon atoms.Representative examples of alkylene include, but are not limited to,—CH₂—, —CH(CH₃)—, —CH(C₂H₅), —CH(CH(CH₃)(C₂H₅))—, —C(H)(CH₃)CH₂CH₂—,—C(CH₃)₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, and —CH₂CH(CH₃)CH₂—

The term “alkynyl” as used herein, means a straight or branched chainhydrocarbon group containing from 2 to 10 carbon atoms and containing atleast one carbon-carbon triple bond. Representative examples of alkynylinclude, but are not limited, to acetylenyl, 1-propynyl, 2-propynyl,1,1-dimethylprop-2-ynyl, 1-propyl-pent-3-ynyl, 3-butynyl, 2-pentynyl,and 1-butynyl.

The term “amino” as used herein, means NH₂, N(H)(alkyl), or N(alkyl)₂.

The term “aminoalkyl” as used herein, means an amino group as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein.

The term “aryl,” as used herein, means phenyl, a bicyclic aryl or atricyclic aryl. The bicyclic aryl is naphthyl, or a phenyl fused to amonocyclic cycloalkyl, or a phenyl fused to a monocyclic cycloalkenyl.Representative examples of the bicyclic aryl include, but are notlimited to, dihydroindenyl, indenyl, naphthyl, dihydronaphthalenyl, andtetrahydronaphthalenyl. The tricyclic aryl is exemplified by a bicyclicaryl fused to a monocyclic cycloalkyl, or a bicyclic aryl fused to amonocyclic cycloalkenyl, or a bicyclic aryl fused to a phenyl.Representative examples of tricyclic aryls include, but are not limitedto, anthracene, phenanthrene, dihydroanthracenyl, fluorenyl,1,2-dihydroacenaphthylenyl, and tetrahydrophenanthrenyl. The phenyl,bicyclic, and tricyclic aryls are attached to the parent molecularmoiety through any carbon atom contained within the phenyl, bicyclic andtricyclic aryls respectively.

The term “arylalkyl” as used herein, means an aryl group, as definedherein, appended to the parent molecular moiety through an alkyl group,as defined herein. Representative examples of arylalkyl include, but arenot limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and2-naphth-2-ylethyl.

The term “cycloalkenyl” as used herein, means monocyclic or bicycliccycloalkenyls containing zero heteroatoms in the ring. The monocycliccycloalkenyl has three-, four-, five-, six-, seven-, or eight carbonatoms and zero heteroatoms. The three or four-membered ring systems haveone double bond, the five- or six-membered ring systems have one or twodouble bonds, and the seven- or eight-membered ring systems have one,two, or three double bonds. Representative examples of monocycliccycloalkenyls include, but are not limited to, cyclohexenyl,2,4-cyclohexadien-1-yl, and 3-cyclopenten-1-yl. Bicyclic cycloalkenylsare exemplified by a monocyclic cycloalkenyl fused to a monocycliccycloalkyl, or a monocyclic cycloalkenyl fused to a monocycliccycloalkenyl. Representative examples of bicyclic cycloalkenyls include,but are not limited to 3a, 4, 5, 6, 7,7a-hexahydro-1H-indenyl,4,5,6,7-tetrahydro-3aH-indene, and octahydronaphthalenyl. Thecycloalkenyl groups of the present invention are appended to the parentmolecular moiety through any substitutable carbon atom within thegroups, and may contain one or two alkylene bridges of 1, 2, 3, or 4carbon atoms, wherein each bridge links two non-adjacent atoms withinthe groups.

The term “cycloalkyl” as used herein, means a saturated, monocyclic orbicyclic ring system. The monocyclic cycloalkyl is a carbocyclic ringsystem containing 3-, 4-, 5-, 6, 7, or 8 carbon atoms and zeroheteroatoms as ring atoms, and zero double bonds. Examples of monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, and cyclooctyl. Bicyclic cycloalkyls are exemplified byfusion of two monocyclic cycloalkyl rings. Representative examples ofbicyclic cycloalkyls include, but are not limited to,bicyclo[4.1.0]heptane, bicyclo[6.1.0]nonane, octahydroindene, anddecahydronaphthalene. The monocyclic and the bicyclic cycloalkyl groupsof the present invention may contain one or two alkylene bridges of 1,2, 3, or 4 carbon atoms, wherein each bridge links two non-adjacentatoms within the groups. Examples of such bridged cycloalkyls include,but are not limited to, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.3.1]nonane, adamantane(tricyclo[3.3.1.1^(3,7)]decane), and noradamantane(octahydro-2,5-methanopentalene). The monocyclic and the bicycliccycloalkyl groups of the present invention can be appended to the parentmolecular moiety through any substitutable carbon atom of the groups.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The “haloalkoxy” as used herein, means an alkoxy group, as definedherein, in which one, two, three, four, five, six, or seven hydrogenatoms are replaced by halogen. Representative examples of haloalkoxyinclude, but are not limited to, fluoromethoxy, 2,2-difluoromethoxy,trifluoromethoxy, and 2-fluoroethoxy.

The term “haloalkyl” as used herein, means an alkyl group, as definedherein, in which one, two, three, four, five, six, or seven hydrogenatoms are replaced by halogen. Representative examples of haloalkylinclude, but are not limited to, chloromethyl, 2-fluoroethyl,2,2-difluoroethyl, trifluoromethyl, 2,2,2-trifluoroethyl,2,2,2-trifluoro-1,1-dimethylethyl, difluoromethyl,3,3,3-trifluoropropyl, pentafluoroethyl, 2-chloro-3-fluoropentyl, and2-iodoethyl.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl ora bicyclic heteroaryl. The monocyclic heteroaryl is a 5- or 6-memberedring containing at least one heteroatom independently selected from thegroup consisting of O, N, and S. The 5-membered ring contains two doublebonds and one, two, three, or four heteroatoms. The 6-membered ringcontains three double bonds and one, two, three or four heteroatoms.Representative examples of monocyclic heteroaryls include, but are notlimited to, furanyl, imidazolyl, isoxazolyl, isothiazolyl, oxadiazolyl,oxazolyl, pyridinyl (including pyridin-2-yl), pyridazinyl, pyrimidinyl,pyrazinyl, pyrazolyl, pyrrolyl, tetrazolyl, thiadiazolyl, thiazolyl(including 1,3-thiazol-2-yl), thienyl, triazolyl, and triazinyl. Thebicyclic heteroaryl is exemplified by a monocyclic heteroaryl fused tophenyl, or a monocyclic heteroaryl fused to a monocyclic cycloalkyl, ora monocyclic heteroaryl fused to a monocyclic cycloalkenyl, or amonocyclic heteroaryl fused to a monocyclic heteroaryl, or a monocyclicheteroaryl fused to a monocyclic heterocycle. Representative examples ofbicyclic heteroaryls include, but are not limited to, benzofuranyl,benzoxadiazolyl, 1,3-benzothiazolyl, benzimidazolyl, benzodioxolyl,benzothienyl, chromenyl, cinnolinyl, furopyridine, indolyl, indazolyl,isoindolyl, isoquinolinyl, naphthyridinyl, oxazolopyridine, quinolinyl,thienopyridine, and thienopyridinyl. The monocyclic and the bicyclicheteroaryl groups are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the groups. The nitrogen and sulfur heteroatoms of theheteroaryl rings may optionally be oxidized, and are contemplated withinthe scope of the invention.

The term “heterocycle” or “heterocyclic” as used herein, means amonocyclic or a bicyclic ring system containing at least one heteroatom.The monocyclic heterocycle is a 3-, 4-, 5-, 6-, 7-, or 8-membered ringcontaining at least one heteroatom in the ring independently selectedfrom the group consisting of O, N, and S. The 3- or 4-membered ringcontains one heteroatom in the ring selected from the group consistingof O, N and S, and optionally one double bond. The 5-membered ringcontains zero or one double bond, and one, two, or three heteroatoms inthe ring independently selected from the group consisting of O, N and S.The 6-, 7-, or 8-membered ring contains zero, one, or two double bonds,and one, two, or three heteroatoms in the ring independently selectedfrom the group consisting of O, N and S. Representative examples ofmonocyclic heterocycles include, but are not limited to, azetidinyl,azepanyl, aziridinyl, diazepanyl, 1,3-dioxanyl, 1,4-dioxanyl,1,3-dioxolanyl, 4,5-dihydroisoxazol-5-yl, 3,4-dihydropyran-6-yl,1,3-dithiolanyl, 1,3-dithianyl, imidazolinyl, imidazolidinyl,isothiazolinyl, isothiazolidinyl, isoxazolinyl, isoxazolidinyl,morpholinyl, oxadiazolinyl, oxadiazolidinyl, oxazolinyl, oxazolidinyl,oxetanyl, piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydropyranyl,tetrahydrothienyl, thiadiazolinyl, thiadiazolidinyl, thiazolinyl,thiazolidinyl, thiomorpholinyl, 1,1-dioxidothiomorpholinyl(thiomorpholine sulfone), thiopyranyl, and trithianyl. The bicyclicheterocycle of the present invention is exemplified by a monocyclicheterocycle fused to a phenyl group, or a monocyclic heterocycle fusedto a monocyclic cycloalkylgroup, or a monocyclic heterocycle fused to amonocyclic cycloalkenyl group, or a monocyclic heterocycle fused to amonocyclic heterocycle group. Representative examples of bicyclicheterocycles include, but are not limited to, 1,3-benzodioxol-4-yl,1,3-benzodithiolyl, 2,3-dihydro-1,4-benzodioxinyl,2,3-dihydro-1-benzofuranyl, 2,3-dihydro-1-benzothienyl,2,3-dihydro-1H-indolyl, and 1,2,3,4-tetrahydroquinolinyl. Theheterocycle groups are connected to the parent molecular moiety throughany substitutable carbon atom or any substitutable nitrogen atomcontained within the group. The monocyclic or bicyclic heterocyclegroups of the present invention may contain an alkenylene bridge of 2,3, or 4 carbon atoms, or one or two alkylene bridges of 1, 2, 3, or 4carbon atoms, wherein each bridge links two non-adjacent carbon atomswithin the groups. Examples of such bridged heterocycles include, butare not limited to, oxaadamantane (2-oxatricyclo[3.3.1.1^(3,7)]decane),octahydro-2,5-epoxypentalene,hexahydro-2H-2,5-methanocyclopenta[b]furan,hexahydro-1H-1,4-methanocyclopenta[c]furan, oxabicyclo[2.2.1]heptane and2,4-dioxabicyclo[4.2.1]nonane. The nitrogen and sulfur heteroatoms inthe heterocycle rings may optionally be oxidized and the nitrogen atomsmay optionally be quarternized.

The term “hydroxyalkyl” as used herein, means an alkyl group, as definedherein, wherein one, two, or three hydrogen atoms are replaced by OH.Representative examples of hydroxyalkyl include, but are not limited to,hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl, and2-ethyl-4-hydroxyheptyl.

The term “oxo” as used herein, means ═O.

b) COMPOUNDS

Compounds of the invention have the formula (I) as described above.

Particular values of variable groups in compounds of formula (I) are asfollows. Such values may be used where appropriate with any of the othervalues, definitions, claims or embodiments defined hereinbefore orhereinafter.

In compounds of formula (I), R² has values as described generally in theSummary.

R², for example, is halogen (e.g. F), alkyl (e.g. C₁₋₃ alkyl such as,but not limited to, methyl), haloalkyl (e.g. trifluoroemthyl), —CN,—O(alkyl) (e.g., —OCH₃), —O(haloalkyl), or —OH.

One embodiment of the invention provides compounds of formula (I)wherein R² is alkyl (e.g. C₁₋₃ alkyl such as, but not limited to,methyl) or halogen. For example, R² is C₁₋₃ alkyl (e.g. methyl),chlorine, or fluorine.

Other embodiment of the invention provides compounds of formula (I)wherein R² is —OH.

Yet other embodiment of the invention provides compounds of formula (I)wherein R² is —O(alkyl). For example, R² is —OCH₃.

Another embodiment of the invention provides compounds of formula (I)wherein R² is haloalkyl. For example, R² is CF₃.

Yet other embodiment of the invention provides compounds of formula (I)wherein R² is —CN.

In certain embodiments, R² and the adjacent carbon atom, together withthe carbon atom to which R² is attached, form a 3-6 membered monocycliccycloalkyl ring that is optionally substituted as described in theSummary. Thus, contemplated in the invention are also compounds offormula (II)

wherein u is 1, 2, 3, or 4; v is 0, 1, 2, 3, or 4; R⁹ is alkyl,hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, haloalkyl, arylalkyl, aryl,aminoalkyl, amino, and halogen, wherein the aryl and the aryl moiety ofthe arylalkyl are each independently unsubstituted or substituted with1, 2, 3, 4, or 5 substituents selected from the group consisting ofalkyl, alkenyl, alkynyl, halogen, OH, O(alkyl), O(haloalkyl), amino, andhaloalkyl; and R¹, R³, R⁴, R⁵, X, m, and n are as described generally inthe Summary.

In compounds of formula (I) or (II), R¹ is phenyl or a monocyclicheteroaryl (for example, pyridinyl or thiazolyl), each of which isoptionally substituted with 1, 2, 3, 4, or 5 substituents as representedby R⁶ groups. One embodiment of the invention provides compounds offormula (I) or (II) wherein R¹ is pyridinyl, optionally substituted asdescribed in the Summary, for example, optionally substituted with oneor two R⁶ groups. Another embodiment of the invention provides compoundsof formula (I) wherein R¹ is formula (I). A further embodiment of theinvention provides compounds of formula (I) or (II) wherein R¹ isformula (ii).

Yet another embodiment of the invention relates to compounds of formula(I) or (II) wherein R¹ is phenyl, optionally substituted as described inthe Summary, for example, optionally substituted with one or two R⁶groups. For example, R¹ is formula (iii). Other example of R¹ is formula(iv).

In certain embodiment, the optional R⁶ group of formula (ii) or (iv) islocated at the 4-position relative to the carbon atom that is attachedto the cycloalkene ring of the parent molecular moiety.

R⁶ in the embodiments described herein above has meanings as describedin the Summary section. Certain embodiments of the invention relate tocompounds of formula (I) or (II) wherein R⁶ is, for example, halogen(e.g. F, Cl), alkyl (e.g. C₁₋₆ alkyl such as, but not limited to,methyl), haloalkyl (e.g. trifluoromethyl), or N(R^(d))(R^(f)) whereinR^(d) and R^(f) are as described in the Summary. For example, R^(d) andR^(f) are each independently hydrogen or C₁₋₆ alkyl such as, but notlimited to, methyl. Further examples of R⁶ include, but are not limitedto, chlorine, fluorine, methyl, trifluoromethyl, and N(C₁₋₆ alkyl)₂.

R³ has values as described generally in the Summary. For example, incompounds of formula (I) or (II), R³ is hydrogen or C₁₋₆ alkyl. Oneembodiment of the invention provides compounds wherein R³ is hydrogen.

R⁴ is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle,wherein each R⁴ is optionally substituted with 1, 2, 3, 4, 5, or 6substituents as represented by R⁷, and R⁷ is as described in the Summarysection.

One embodiment of the invention provides compounds of formula (I) or(II) wherein R⁴ is optionally substituted phenyl.

Another embodiment of the invention provides compounds of formula (I) or(II) wherein R⁴ is optionally substituted heteroaryl.

Yet another embodiment of the invention provides compounds of formula(I) or (II) wherein R⁴ is optionally substituted monocyclic heteroaryl(e.g. pyridinyl).

Further, other embodiment of the invention provides compounds wherein R⁴is phenyl or monocyclic heteroaryl, and each R⁴ is optionallysubstituted as disclosed in the Summary and in embodiments describedherein.

In certain embodiments, R⁴ is optionally substituted with one or two R⁷groups.

In certain embodiments, R⁴ is substituted with one or two R⁷ groups, andthat at least one of the R⁷ groups is attached to the 4-position of thephenyl or the monocyclic heteroaryl ring relative to the carbon atomthat is attached to the nitrogen atom of the parent molecular moiety.

Examples of R⁷ include, but are not limited to, alkyl (e.g. C₁₋₆ alkylsuch as, but not limited to, isopropyl, tert-butyl), halogen (e.g. Cl,F), —OR^(a), —SF₅, —S(O)₂R^(b), —N(R^(a))(R^(c)), haloalkyl (e.g.trifluoromethyl, 2,2,2-trifluoromethyl-1-methylethyl), and—(CR^(j)R^(k))_(p)—CN, wherein R^(a), R^(b), R^(j), R^(k), and p are asdescribed in the Summary section. R^(a) and R^(b), for example, are eachindependently alkyl (e.g. methyl) or haloalkyl (e.g. trifluoromethyl).R^(j) and R^(k), for example, are each independently hydrogen or C₁₋₆alkyl (e.g. methyl). p, for example, is 1 or 2. In certain embodiments,p is 1. One embodiment of the invention relate to compounds wherein R⁷is tert-butyl, isopropyl, chlorine, fluorine, —O(CF₃), —SF₅,—S(O)₂(CF₃), —NH₂, —N(H)(CH₃), —N(CH₃)₂, —CF₃, and—(CR^(j)R^(k))_(p)—CN, and R^(j), R^(k), and p are as described in theSummary and in embodiments described herein above.

One embodiment of the invention relates to compounds wherein n is 0.

Yet other embodiment of the invention provides compounds of formula (I)or (II) wherein n is 1.

R⁵ has values as described generally in the Summary.

Certain embodiment of the invention includes, but is not limited to,compounds of formula (I) or (II) wherein R⁵, if present, is alkyl suchas, but not limited to, C₁₋₃ alkyl. For example, R⁵ is methyl.

Certain embodiment of the invention provides compounds of formula (I) or(II) wherein X is O.

Other embodiment of the invention provides compounds of formula (I) or(II) wherein X is S.

Yet another embodiment relates to compounds of formula (I) or (II)wherein X is N(R^(z)) wherein R^(z) is hydrogen, alkyl, or CN.

m is 0, 1, or 2. In one embodiment, m is 1. It is to be understood thatwhen m is 1 in formula (I), this refers to compounds of formula (Ia)

wherein R¹, R², R³, R⁴, R⁵, X, and n have the values as set forth in theSummary and the Detailed description sections. Embodiments for R¹, R²,R³, R⁴, R⁵, X, and n, and combinations of embodiments, includingparticular, and more particular embodiments as described for formula (I)are also contemplated for compounds of formula (Ia).

It is appreciated that the present invention contemplates compounds offormula (I), (Ia), or (II) with combinations of the above embodiments,including particular, more particular and preferred embodiments.

Accordingly, one aspect of the invention relates to a group of compoundsof formula (I) or (II) wherein X is O, and m is 1.

Other examples of a group of compounds of formula (I) or (II) includethose wherein X is S, and m is 1.

Other examples of a group of compounds of formula (I) or (II) includethose wherein X is N(R^(z)), and m is 1.

Yet other examples of a group of compounds of formula (I) or (II)include those wherein X is O, and m is 2.

Further examples of a group of compounds of formula (I) or (II) includethose wherein X is S, and m is 2.

Another examples of a group of compounds of formula (I) or (II) includethose wherein X is N(R^(z)), and m is 2.

Yet further examples of a group of compounds of formula (I) or (II)include those wherein X is O, and m is 0.

Yet other examples of a group of compounds of formula (I) or (II)include those wherein X is S, and m is 0.

Yet another examples of a group of compounds of formula (I) or (II)include those wherein X is N(R^(z)), and m is 0.

Within each group of compounds of formula (I), (Ia), or (II) asdescribed in the preceding paragraphs, R¹, R², R³, R⁴, R⁵, R^(z), and nhave values as defined in the Summary.

Thus, of each group of compounds of formula (I), (Ia), or (II) asdescribed in the preceding paragraphs, examples of a subgroup includethose wherein R¹ is optionally substituted monocyclic heteroaryl. Forexample, R¹ is pyridinyl or thiazolyl, optionally substituted asdescribed in the Summary. In one embodiment, R¹ is substitutedpyridinyl, optionally substituted as described in the Summary, forexample, optionally substituted with one or two substituents, R⁶. Otherembodiment relates to compounds wherein R¹ is formula (i). Yet otherembodiment relates to compounds wherein R¹ is formula (ii).

Other examples of a subgroup include those wherein R¹ is optionallysubstituted phenyl. For example, R¹ is formula (iii). Further example ofR¹ is formula (iv).

Of all examples of the groups and subgroups of compounds of formula (I),(Ia), or (II) as discussed herein-above, R², R³, R⁴, R^(z), R⁵, n, andthe optional substituents of R¹ have the meanings as described in theSummary and the Detailed Description.

For example, for each of the foregoing groups and subgroups ofcompounds, examples of the optional substituents (R⁶) of R¹ include, butare not limited to, halogen (e.g. F, Cl), alkyl (e.g. C₁₋₆ alkyl suchas, but not limited to, methyl), haloalkyl (e.g. trifluoromethyl), orN(R^(d))(R^(f)) wherein R^(d) and R^(f) are as described in the Summary.For example, R^(d) and R^(f) are each independently hydrogen or C₁₋₆alkyl such as, but not limited to, methyl. Further examples of R⁶include, but are not limited to, chlorine, fluorine, methyl,trifluoromethyl, and N(C₁₋₆ alkyl)₂. R⁴, for example, is phenyl,optionally substituted as described in the Summary section, for example,optionally substituted with one or two R⁷. Yet other examples of R⁴ isphenyl substituted with one or two R⁷ groups, wherein at least one ofthe R⁷ is located at the 4-position of the phenyl ring relative to thecarbon atom that is attached to the nitrogen atom of formula (I), (Ia),or (II). Further examples of R⁴ include, but are not limited to,heteroaryl (e.g. monocyclic heteroaryl such as, but not limited to,pyridinyl), optionally substituted as described in the Summary and inthe Detailed Description sections. Certain embodiment of the inventionrelates to compounds wherein the heteroaryl is optionally substitutedwith one or two R⁷ groups. Yet certain embodiment relates to compoundsof formula (I), (Ia), or (II) wherein R⁴ is monocyclic heteroaryl (forexample, pyridinyl), substituted with one or two substituents, whereinat least one of the optional substituents, R⁷, is located on the4-position of the ring relative to the carbon that is attached to thenitrogen atom of formula (I), (Ia), or (II). Examples of R⁷ are asdescribed in the Summary and in the Detailed Description sections.Certain embodiment of the invention pertains to compounds wherein R⁵, ifpresent, is alkyl such as, but not limited to, C₁₋₃ alkyl. n, forexample, is 1. Yet other embodiment includes compounds of formula (I),(Ia), or (II) wherein n is 0. R² is, for example, halogen (e.g. F),alkyl (e.g C₁₋₃ alkyl such as, but not limited to, methyl), haloalkyl(e.g. trifluoromethyl), —CN, —O(alkyl) (e.g. OCH₃), —O(haloalkyl), or—OH. Certain embodiments of the invention include compounds of formula(I) or (Ia) wherein R² is, for example, halogen (e.g. F) or alkyl (e.g.C₁₋₃ alkyl such as, but not limited to, methyl). For example, R² is C₁₋₃alkyl (e.g. methyl), chlorine, or fluorine. In one embodiment, R² ishalogen such as, but not limited to, fluorine or chlorine. In anotherembodiment, R² is —OH. In yet another embodiment, R² is —O(alkyl) suchas, but not limited to, —OCH₃—In yet another embodiment, R² is haloalkylsuch as, but not limited to, trifluoromethyl. In yet another embodiment,R² is —CN. Included in the invention are also compounds of formula (I)or (Ia) wherein R² and the adjacent carbon atom, together with thecarbon atom to which R² is attached, form a 3-6 membered monocycliccycloalkyl ring that is optionally substituted as described in theSummary and the Detailed Description sections. R³, for each group andsubgroup of compounds of formula (I), (Ia), or (II) as described aboveis hydrogen or C₁₋₆ alkyl. One embodiment of the invention providescompounds of formula (I), (Ia), or (II) wherein R³ is hydrogen.

Yet another aspect of the invention relates to compounds of formula (I)wherein R¹ is formula (i), X is O, m is 1, R³ is hydrogen, and R⁴ isphenyl. Accordingly, one embodiment of the invention provides compoundsof formula (III)

wherein R², R⁵, R⁶, R⁷ and n are as disclosed in the Summary and theDetailed Description sections. It is understood that embodiments for R²,R⁵, R⁶, R⁷ and n, and combinations of embodiments, including particular,and more particular embodiments as described for formula (I), (Ia) or(II) are also contemplated for compounds of formula (III).

Compounds of the present invention contain one or more asymmetricallysubstituted carbon atoms in the cycloalkene ring of formula (I), (Ia),(II) and (III). For example, compounds of formula (I) and (III) can havestereoisomers including, but not limited to, those shown below:

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, m, and n are as disclosed in theSummary and the Detailed Description sections. It is understood thatembodiments for R¹, R², R³, R⁴, R⁵, R⁶, R⁷, X, m, and n, andcombinations of embodiments, including particular, and more particularembodiments as described for formula (I), (Ia) or (II), are alsocontemplated for compounds of formula (Ib), (Ic), (IIIa), and (IIIb).When n is 1, the carbon atom to which R⁵ group is attached can have (R)or (S) configuration. The terms “R” and “S” used herein areconfigurations as defined in IUPAC 1974 Recommendations for Section E,Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45: 13-30. Thepresent invention contemplates various individual stereoisomers(including enantiomers and diastereomers) and mixtures thereof.Individual stereoisomers of compounds of the present invention may beprepared synthetically from commercially available starting materialsthat contain asymmetric or chiral centers or by preparation of racemicmixtures followed by resolution of the individual stereoisomer usingmethods that are known to those of ordinary skill in the art. Examplesof resolution are, for example, (i) attachment of a mixture ofenantiomers to a chiral auxiliary, separation of the resulting mixtureof diastereomers by recrystallization or chromatography, followed byliberation of the optically pure product; or (ii) separation of themixture of enantiomers or diastereomers on chiral chromatographiccolumns.

The invention also contemplates the various geometric isomers andmixtures thereof resulting from the disposition of substituents around acarbon-carbon double bond, a carbon-nitrogen double bond, a cycloalkylgroup, or a heterocycle group. Substituents around a carbon-carbondouble bond or a carbon-nitrogen bond are designated as being of Z or Econfiguration and substituents around a cycloalkyl or heterocycle aredesignated as being of cis or trans configuration.

Within the present invention it is to be understood that compoundsdisclosed herein may exhibit the phenomenon of tautomerism and alltautomeric isomers are included in the scope of the invention.

Exemplary compounds of the present invention include, but are notlimited to,

-   4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide;-   N-(4-chlorophenyl)-4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-ene-1-carboxamide;-   4-(3-chloropyridin-2-yl)-4-fluoro-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide;-   N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-ene-1-carboxamide;-   4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethoxy)phenyl]cyclohex-1-ene-1-carboxamide;-   4-(3-chloropyridin-2-yl)-N-[4-(1-cyano-1-methylethyl)phenyl]-4-fluorocyclohex-1-ene-1-carboxamide;-   4-(3-chloropyridin-2-yl)-4-methoxy-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide;-   4-(3-chloropyridin-2-yl)-4-methoxy-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide;-   4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide;-   4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-(trifluoromethoxy)phenyl]cyclohex-1-ene-1-carboxamide;-   4-fluoro-4-(3-methylpyridin-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide;-   N-(4-chlorophenyl)-4-fluoro-4-(3-methylpyridin-2-yl)cyclohex-1-ene-1-carboxamide;-   N-(4-tert-butylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl)cyclohex-1-ene-1-carboxamide;-   4-fluoro-4-(3-fluoropyridin-2-yl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide;-   N-(4-tert-butylphenyl)-4-fluoro-4-(3-fluoropyridin-2-yl)cyclohex-1-ene-1-carboxamide;-   4-fluoro-4-(3-fluoropyridin-2-yl)-N-[5-(trifluoromethyl)pyridin-2-yl]cyclohex-1-ene-1-carboxamide;-   4-fluoro-4-(3-fluoropyridin-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide;-   4-fluoro-4-(3-fluoropyridin-2-yl)-N-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]cyclohex-1-ene-1-carboxamide;-   4-fluoro-4-(1,3-thiazol-2-yl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide;-   4-fluoro-4-(1,3-thiazol-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide;-   (4R)—N-(4-chlorophenyl)-4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-ene-1-carboxamide;-   (4S)—N-(4-chlorophenyl)-4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-ene-1-carboxamide;-   (4R)-4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide;-   (4S)-4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide;-   4-[3-(dimethylamino)pyridin-2-yl]-4-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide;-   4-fluoro-4-(1,3-thiazol-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide;-   (4R)-4-(3-chloropyridin-2-yl)-4-fluoro-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide;-   (4S)-4-(3-chloropyridin-2-yl)-4-fluoro-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide;-   N-{4-[(difluoromethyl)sulfonyl]phenyl}-4-fluoro-4-(3-fluoropyridin-2-yl)cyclohex-1-ene-1-carboxamide;-   4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]cyclohex-1-ene-1-carboxamide;-   4-(3-chloropyridin-2-yl)-4-fluoro-6-methyl-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide;-   4-(3-chloropyridin-2-yl)-4-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide;-   4-(3-chloropyridin-2-yl)-4-fluoro-N-(4-isopropylphenyl)cyclohex-1-ene-1-carboxamide;-   4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(2,2,2-trifluoro-1-methylethyl)phenyl]cyclohex-1-ene-1-carboxamide;-   6-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}bicyclo[4.1.0]hept-3-ene-3-carboxamide;-   4-(3-chloropyridin-2-yl)-4-fluoro-6-methyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide;    and-   4-(3-chloropyridin-2-yl)-4-methyl-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide;-   N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-4-methylcyclohex-1-ene-1-carboxamide.

c. BIOLOGICAL DATA (i) In Vitro Data—Determination of InhibitionPotencies

Dulbecco's modified Eagle medium (D-MEM) (with 4.5 mg/mL glucose) andfetal bovine serum were obtained from Hyclone Laboratories, Inc. (Logan,Utah). Dulbecco's phosphate-buffered saline (D-PBS) (with 1 mg/mLglucose and 3.6 mg/1 Na pyruvate, without phenol red), L-glutamine,hygromycin B, and Lipofectamine® were obtained from Life Technologies(Grand Island, N.Y.). G418 sulfate was obtained fromCalbiochem-Novabiochem Corp. (San Diego, Calif.). Capsaicin(8-methyl-N-vanillyl-6-nonenamide) was obtained from Sigma-Aldrich, Co.(St. Louis, Mo.). Fluo-4 AM(N-[4-[6-[(acetyloxy)methoxy]-2,7-difluoro-3-oxo-3H-xanthen-9-yl]-2-[2-[2-[bis[2-[(acetyloxy)methoxy]-2-oxyethyl]amino]-5-methylphenoxy]ethoxy]phenyl]-N-[2-[(acetyloxy)methoxy]-2-oxyethyl]-glycine,(acetyloxy)methyl ester) was purchased from Molecular Probes (Eugene,Oreg.).

The cDNAs for the human TRPV 1 receptor were isolated by reversetranscriptase-polymerase chain reaction (RT-PCR) from human smallintestine poly A+RNA supplied by Clontech (Palo Alto, Calif.) usingprimers designed surrounding the initiation and termination codonsidentical to the published sequences (Hayes et al. Pain Vol. 88 pages205-215, 2000). The resulting cDNA PCR products were subcloned intopCIneo mammalian expression vector (Promega) and fully sequenced usingfluorescent dye-terminator reagents (Prism, Perkin-Elmer AppliedBiosystems Division) and a Perkin-Elmer Applied Biosystems Model 373 DNAsequencer or Model 310 genetic analyzer. Expression plasmids encodingthe hTRPV1 cDNA were transfected individually into 1321N1 humanastrocytoma cells using Lipofectamine®. Forty-eight hours aftertransfection, the neomycin-resistant cells were selected with growthmedium containing 800 μg/mL Geneticin (Gibco BRL). Surviving individualcolonies were isolated and screened for TRPV1 receptor activity. Cellsexpressing recombinant homomeric TRPV1 receptors were maintained at 37°C. in D-MEM containing 4 mM L-glutamine, 300 μg/mL G418 (Cal-biochem)and 10% fetal bovine serum under a humidified 5% CO₂ atmosphere.

The functional activity of compounds at the TRPV1 receptor wasdetermined with a Ca²⁺ influx assay and measurement of intracellularCa²⁺ levels ([Ca²⁺]_(i)). All compounds were tested over an 11-pointhalf-log concentration range. Compound solutions were prepared in D-PBS(4× final concentration), and diluted serially across 96-well v-bottomtissue culture plates using a Biomek 2000 robotic automation workstation(Beckman-Coulter, Inc., Fullerton, Calif.). A 0.2 μM solution of theTRPV1 agonist capsaicin was also prepared in D-PBS. The fluorescent Ca²⁺chelating dye Fluo-4 AM was used as an indicator of the relative levelsof [Ca²⁺]_(i) in a 96-well format using a Fluorescence Imaging PlateReader (FLIPR)(Molecular Devices, Sunnyvale, Calif.). Cells were grownto confluency in 96-well black-walled tissue culture plates. Then, priorto the assay, the cells were loaded with 100 μL per well of Fluo-4 AM (2μM, in D-PBS) for 1-2 hours at 23° C. Washing of the cells was performedto remove extracellular Fluo-4 AM (2×1 mL D-PBS per well), andafterward, the cells were placed in the reading chamber of the FLIPRinstrument. 50 μL of the compound solutions were added to the cells atthe 10 second time mark of the experimental run. Then, after a 3-minutetime delay, 50 μL of the capsaicin solution was added at the, 190seconds time mark (0.05 μM final concentration) (final volume=200 μL) tochallenge the TRPV1 receptor. Time length of the experimental run was240 seconds. Fluorescence readings were made at 1 to 5 second intervalsover the course of the experimental run. The peak increase in relativefluorescence units (minus baseline) was calculated from the 190 secondstime mark to the end of the experimental run, and expressed as apercentage of the 0.05 μM capsaicin (control) response. Curve-fits ofthe data were solved using a four-parameter logistic Hill equation inGraphPad Prism® (GraphPad Software, Inc., San Diego, Calif.), and IC₅₀values were calculated.

Certain compounds of the invention were tested in the assay describedabove and are effective TRPV1 antagonists with IC₅₀ values from about 10μM to about 10 nM, for example, from about 1 μM to about 10 nM, andpreferably, from about 100 nM to about 10 nM.

(ii) In Vivo Data-Assessment of Osteoarthritic Pain

Unilateral knee joint osteoarthritis was induced in male Sprague Dawleyrats by a single intra-articular (i.a.) injection of sodiummonoiodoacetate (Sigma, St. Louis, Mo.) (3 mg in 0.05 mL sterileisotonic saline) into the joint cavity using a 26G needle under light(2-4%) isoflurane anesthesia. Following injection, the animals wereallowed to recover from the effects of anesthesia (usually 5-10 min)before returning them to their home cages. After approximately 21 days,test compound was administered orally. Grip strength was assessed as ameasure of activity-induced pain in osteoarthritic rats one hour afteradministration of test compound. Measurements of hind limb grip forcewere conducted by recording the maximum compressive force (CF_(max))exerted on the hind limb strain gauge, in a commercially available gripforce measurement system (Columbus Instruments, Columbus, Ohio). Duringtesting, each rat was gently restrained and allowed to grasp the wiremesh frame attached to the strain gauge. The experimenter then moved theanimal in a rostral-to-caudal direction until the grip was broken. Eachrat was sequentially tested twice at an approximately 2-3 min intervalto obtain a raw mean grip force (CF_(max) in gram force units). In orderto account for the body weight differences among the rats, this raw meangrip force was converted to a maximum hind limb compressive force foreach animal by dividing the CF_(max) by the body weight of the rat in kg[(CF_(max) in gram force)/kg body weight]. A group of age matched naïveanimals was included in each experiment. Each dose experiment included 6naïve rats, 6 vehicle-controlled rats and 6 drug-administered rats. Thedata obtained from various dose groups for the test compound werecompared with data from the naïve group. The vehicle control group wasassigned a value of 0% whereas the naïve group was assigned a value of100%. The effects for each dose-group were expressed as % return tonormal grip force as found in the naïve group.

Certain compounds of the invention were tested using the generalprotocol as outlined above and exhibited efficacy in relieving pain. Forexample, at the concentration of 100 μmol/kg these compounds providedpain relief as measured by 30% to about 80% return to normal grip forcefor the group of animals that received the drug compared to the vehiclecontrol group.

d. METHODS OF USING THE COMPOUNDS

One embodiment of the present invention provides a method for treating adisorder that may be ameliorated by inhibiting vanilloid receptorsubtype 1 (TRPV1) receptor in a host mammal in need of such treatment.The method comprises administering a therapeutically effective amount ofa compound of formula (I) or a pharmaceutically acceptable salt thereof.

Another embodiment of the present invention provides a method fortreating pain in a mammal in need of such treatment. This methodcomprises administering a therapeutically effective amount of a compoundof formula (I) according to claim 1 or a pharmaceutically acceptablesalt thereof.

Yet another embodiment of the present invention provides a method oftreating ischemia including acute cerebral ischemia, pain includingchronic pain, neuropathic pain, nociceptive pain, allodynia,inflammatory pain, inflammatory hyperalgesia, post herpetic neuralgia,neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy,nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns,back pain, visceral pain, cancer pain, dental pain, headache, migraine,carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvichypersensitivity, pelvic pain, menstrual pain, bladder disease, such asincontinence and bladder overactivity, micturition disorder, renalcolic; and cystitis; inflammation such as burns, rheumatoid arthritisand osteoarthritis; neurodegenerative disease such as stroke, poststroke pain and multiple sclerosis; pulmonary disease such as asthma,cough, chronic obstructive pulmonary disease (COPD) andbronchoconstriction; gastrointestinal disease such as gastroesophagealreflux disease (GERD), dysphagia, ulcer, irritable bowel syndrome (IBS),inflammatory bowel disease (IBD), colitis and Crohn's disease; ischemiasuch as cerebrovascular ischemia; emesis such as cancerchemotherapy-induced emesis, and obesity, in mammals, especially humans.For example, the compounds of the invention are useful for the treatmentof pain, particularly nociceptive and inflammatory pain. This methodcomprises the step of administering a therapeutically effective amountof a compound of formula (I) or a pharmaceutically acceptable saltthereof, to a subject in need thereof.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used to treat pain as demonstrated byNolano, M. et al., Pain 81 (1999) 135; Caterina, M. J. and Julius, D.,Annu. Rev. Neurosci. 24, (2001) 487-517; Caterina, M. J. et al., Science288 (2000) 306-313; Caterina, M. J. et al., Nature 389 (1997) 816-824.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used to treat bladder overactivityand/or urinary incontinence as demonstrated by Fowler, C. Urology 55(2000) 60.

Compounds of the present invention, including but not limited to thosespecified in the examples, can be used to treat inflammatory thermalhyperalgesia as demonstrated by Davis, J. et al., Nature 405 (2000)183-187.

Compounds of the invention may be administered alone, or in combinationwith one or more other compounds of the invention, or in combination(i.e. co-administered) with one or more additional pharmaceuticalagents. For example, a compound of formula (I) or a pharmaceuticallyacceptable salt or solvate thereof, may be administered in combinationwith acetaminophen, or with one or more nonsteroidal anti-inflammatorydrug (NSAID), or combination thereof. Examples of the nonsteroidalanti-inflammatory drug (NSAID) include, but are not limited to, aspirin,diclofenac, diflusinal, etodolac, fenbufen, fenoprofen, flufenisal,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac,meclofenamic acid, mefenamic acid, meloxicam, nabumetone, naproxen,nimesulide, nitroflurbiprofen, olsalazine, oxaprozin, phenylbutazone,piroxicam, sulfasalazine, sulindac, tolmetin and zomepirac. Combinationtherapy includes administration of a single pharmaceutical dosageformulation containing one or more of the compounds of invention and oneor more additional pharmaceutical agents, as well as administration ofthe compounds of the invention and each additional pharmaceutical agent,in its own separate pharmaceutical dosage formulation. For example, acompound of the invention and one or more additional pharmaceuticalagents, may be administered to the patient together, in a single oraldosage composition having a fixed ratio of each active ingredient, suchas a tablet or capsule; or each agent may be administered in separateoral dosage formulations.

Where separate dosage formulations are used, compounds of the inventionand one or more additional pharmaceutical agents may be administered atessentially the same time (e.g. concurrently) or at separately staggeredtimes (e.g. sequentially).

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention can be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated and the condition and prior medical historyof the patient being treated. However, it is within the skill of the artto start doses of the compound at levels lower than required to achievethe desired therapeutic effect and to gradually increase the dosageuntil the desired effect is achieved.

Compounds of the invention can also be administered as a pharmaceuticalcomposition comprising the compounds of interest in combination with oneor more pharmaceutically acceptable carriers. The phrase“therapeutically effective amount” of the compound of the inventionmeans a sufficient amount of the compound to treat disorders, at areasonable benefit/risk ratio applicable to any medical treatment. Itwill be understood, however, that the total daily usage of the compoundsand compositions of the invention will be decided by the attendingphysician within the scope of sound medical judgment. The specifictherapeutically effective dose level for any particular patient willdepend upon a variety of factors including the disorder being treatedand the severity of the disorder; activity of the specific compoundemployed; the specific composition employed; the age, body weight,general health, sex and diet of the patient; the time of administration,route of administration, and rate of excretion of the specific compoundemployed; the duration of the treatment; drugs used in combination orcoincidental with the specific compound employed; and like factorswell-known in the medical arts. For example, it is well within the skillof the art to start doses of the compound at levels lower than requiredto achieve the desired therapeutic effect and to gradually increase thedosage until the desired effect is achieved.

The total daily dose of the compounds of this invention may beadministered to a human or a lower animal ranging from about 0.10 μg/kgbody weight to about 40 mg/kg body weight. More preferable doses can bein the range of from about 0.10 μg/kg body weight to about 5 mg/kg bodyweight. If desired, the effective daily dose can be divided intomultiple doses for purposes of administration. Consequently, single dosecompositions may contain such amounts or submultiples thereof to make upthe daily dose.

e. PHARMACEUTICAL COMPOSITIONS

The present invention further provides pharmaceutical compositions thatcomprise compounds of the present invention or a pharmaceuticallyacceptable salt or solvate thereof. The pharmaceutical compositionscomprise compounds of the present invention that may be formulatedtogether with one or more non-toxic pharmaceutically acceptablecarriers.

Another aspect of the present invention is a pharmaceutical compositioncomprising a compound of the invention, or a pharmaceutically acceptablesalt or solvate thereof, and one or more pharmaceutically acceptablecarriers, alone or in combination with acetaminophen, or with one ormore nonsteroidal anti-inflammatory drug (NSAID), or a combinationthereof.

The pharmaceutical compositions of this invention can be administered tohumans and other mammals orally, rectally, parenterally,intracisternally, intravaginally, intraperitoneally, topically (as bypowders, ointments or drops), bucally or as an oral or nasal spray. Theterm “parenterally” as used herein, refers to modes of administrationwhich include intravenous, intramuscular, intraperitoneal, intrasternal,subcutaneous and intraarticular injection and infusion.

The term “pharmaceutically acceptable carrier” as used herein, means anon-toxic, inert solid, semi-solid or liquid filler, diluent,encapsulating material or formulation auxiliary of any type. Someexamples of materials which can serve as pharmaceutically acceptablecarriers are sugars such as, but not limited to, lactose, glucose andsucrose; starches such as, but not limited to, corn starch and potatostarch; cellulose and its derivatives such as, but not limited to,sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate;powdered tragacanth; malt; gelatin; talc; excipients such as, but notlimited to, cocoa butter and suppository waxes; oils such as, but notlimited to, peanut oil, cottonseed oil, safflower oil, sesame oil, oliveoil, corn oil and soybean oil; glycols; such a propylene glycol; esterssuch as, but not limited to, ethyl oleate and ethyl laurate; agar;buffering agents such as, but not limited to, magnesium hydroxide andaluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline;Ringer's solution; ethyl alcohol, and phosphate buffer solutions, aswell as other non-toxic compatible lubricants such as, but not limitedto, sodium lauryl sulfate and magnesium stearate, as well as coloringagents, releasing agents, coating agents, sweetening, flavoring andperfuming agents, preservatives and antioxidants can also be present inthe composition, according to the judgment of the formulator.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous carriers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol and the like), vegetable oils (such as olive oil), injectableorganic esters (such as ethyl oleate) and suitable mixtures thereof.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents and dispersing agents. Prevention ofthe action of microorganisms can be ensured by the inclusion of variousantibacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid and the like. It may also be desirableto include isotonic agents such as sugars, sodium chloride and the like.Prolonged absorption of the injectable pharmaceutical form can bebrought about by the inclusion of agents which delay absorption such asaluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug, it isdesirable to slow the absorption of the drug from subcutaneous orintramuscular injection. This can be accomplished by the use of a liquidsuspension of crystalline or amorphous material with poor watersolubility. The rate of absorption of the drug then depends upon itsrate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders and granules. In such solid dosage forms, the activecompound may be mixed with at least one inert, pharmaceuticallyacceptable excipient or carrier, such as sodium citrate or dicalciumphosphate and/or a) fillers or extenders such as starches, lactose,sucrose, glucose, mannitol and silicic acid; b) binders such ascarboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose and acacia; c) humectants such as glycerol; d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates and sodium carbonate; e) solutionretarding agents such as paraffin; f) absorption accelerators such asquaternary ammonium compounds; g) wetting agents such as cetyl alcoholand glycerol monostearate; h) absorbents such as kaolin and bentoniteclay and i) lubricants such as talc, calcium stearate, magnesiumstearate, solid polyethylene glycols, sodium lauryl sulfate and mixturesthereof. In the case of capsules, tablets and pills, the dosage form mayalso comprise buffering agents.

Solid compositions of a similar type may also be employed as fillers insoft and hard-filled gelatin capsules using such carriers as lactose ormilk sugar as well as high molecular weight polyethylene glycols and thelike.

The solid dosage forms of tablets, dragees, capsules, pills and granulescan be prepared with coatings and shells such as enteric coatings andother coatings well-known in the pharmaceutical formulating art. Theymay optionally contain opacifying agents and may also be of acomposition such that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, ifappropriate, with one or more of the above-mentioned carriers.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, groundnut, corn,germ, olive, castor and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan andmixtures thereof.

Besides inert diluents, the oral compositions may also include adjuvantssuch as wetting agents, emulsifying and suspending agents, sweetening,flavoring and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, tragacanth and mixtures thereof.

Compositions for rectal or vaginal administration are preferablysuppositories which can be prepared by mixing the compounds of thisinvention with suitable non-irritating carriers or carriers such ascocoa butter, polyethylene glycol or a suppository wax which are solidat room temperature but liquid at body temperature and therefore melt inthe rectum or vaginal cavity and release the active compound.

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals which are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients and the like. The preferred lipids are natural and syntheticphospholipids and phosphatidyl cholines (lecithins) used separately ortogether.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

Dosage forms for topical administration of a compound of this inventioninclude powders, sprays, ointments and inhalants. The active compoundmay be mixed under sterile conditions with a pharmaceutically acceptablecarrier and any needed preservatives, buffers or propellants which maybe required. Opthalmic formulations, eye ointments, powders andsolutions are also contemplated as being within the scope of thisinvention.

The compounds of the present invention can be used in the form ofpharmaceutically acceptable salts derived from inorganic or organicacids. The phrase “pharmaceutically acceptable salt” means those saltswhich are, within the scope of sound medical judgement, suitable for usein contact with the tissues of humans and lower animals without unduetoxicity, irritation, allergic response and the like and arecommensurate with a reasonable benefit/risk ratio.

Pharmaceutically acceptable salts are well known in the art. Forexample, S. M. Berge et al. describe pharmaceutically acceptable saltsin detail in (J. Pharmaceutical Sciences, 1977, 66: 1 et seq). The saltscan be prepared in situ during the final isolation and purification ofthe compounds of the invention or separately by reacting a free basefunction with a suitable organic acid. Representative acid additionsalts include, but are not limited to acetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxyethansulfonate (isothionate),lactate, malate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, palmitoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, phosphate, glutamate, bicarbonate, p-toluenesulfonate andundecanoate. Also, the basic nitrogen-containing groups can bequaternized with such agents as lower alkyl halides such as, but notlimited to, methyl, ethyl, propyl, and butyl chlorides, bromides andiodides; dialkyl sulfates like dimethyl, diethyl, dibutyl and diamylsulfates; long chain halides such as, but not limited to, decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides; arylalkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained. Examples of acids which canbe employed to form pharmaceutically acceptable acid addition saltsinclude such inorganic acids as hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid and such organic acids as aceticacid, fumaric acid, maleic acid, 4-methylbenzenesulfonic acid, succinicacid and citric acid.

Basic addition salts can be prepared in situ during the final isolationand purification of compounds of this invention by reacting a carboxylicacid-containing moiety with a suitable base such as, but not limited to,the hydroxide, carbonate or bicarbonate of a pharmaceutically acceptablemetal cation or with ammonia or an organic primary, secondary ortertiary amine. Pharmaceutically acceptable salts include, but are notlimited to, cations based on alkali metals or alkaline earth metals suchas, but not limited to, lithium, sodium, potassium, calcium, magnesiumand aluminum salts and the like and nontoxic quaternary ammonia andamine cations including ammonium, tetramethylammonium,tetraethylammonium, methylamine, dimethylamine, trimethylamine,triethylamine, diethylamine, ethylamine and the like. Otherrepresentative organic amines useful for the formation of base additionsalts include ethylenediamine, ethanolamine, diethanolamine, piperidine,piperazine and the like.

The term “pharmaceutically acceptable prodrug” or “prodrug” as usedherein, represents those prodrugs of the compounds of the presentinvention which are, within the scope of sound medical judgement,suitable for use in contact with the tissues of humans and lower animalswithout undue toxicity, irritation, allergic response, and the like,commensurate with a reasonable benefit/risk ratio, and effective fortheir intended use.

The present invention contemplates compounds of the invention formed bysynthetic means or formed by in vivo biotransformation of a prodrug.

The compounds of the invention can exist in unsolvated as well assolvated forms, including hydrated forms, such as hemi-hydrates. Ingeneral, the solvated forms, with pharmaceutically acceptable solventssuch as water and ethanol among others are equivalent to the unsolvatedforms for the purposes of the invention.

f. GENERAL SYNTHESIS

This invention is intended to encompass compounds of the invention whenprepared by synthetic processes or by metabolic processes. Preparationof the compounds by metabolic processes includes those occurring in thehuman or animal body (in vivo) or processes occurring in vitro.

The compounds of the invention may be prepared by a variety of processeswell known for the preparation of compounds of this class. For example,the compounds of the invention wherein the groups R¹, R², R³, R⁴, R⁵, m,n, and X have the meanings as set forth in the summary section unlessotherwise noted, can be synthesized as shown in Schemes 1-7.

As used in the descriptions of the schemes and the examples, certainabbreviations are intended to have the following meanings: EtOAc forethyl acetate; 9-BBN for 9-borabicylco[3.3.1]nonane, DMF forN,N-dimethylformamide, DMP for Dess-Martin periodinane; DAST fordiethylaminosulfur trifluoride; DMSO for dimethyl sulfonamide, LiHMDSfor lithium bis(trimethylsilyl)amide; OTf for trifluoromethylsulfonate,TBAF for tetrabutyl ammonium fluoride, and THF for tetrahydrofuran.

Compounds of general formula (I) wherein X is O and m is 1 can beprepared using general procedures as illustrated in Scheme 1.

Compounds of formula (4) can be prepared from ketals of formula (1) orfrom enones of formula (6). For example, compounds of formula (1) can bereacted with an acid to provide ketones of formula (2). Examples ofsuitable acid for the conversion are inorganic acid such as, but notlimited to, trifluoroacetic acid, an inorganic acid such as, but notlimited to, hydrochloric acid, or mixtures thereof. The reaction isgenerally conducted in a solvent such as, but not limited to,dichloromethane, THF, dioxane, or mixtures thereof, at a temperature ofabout room temperature to about 60° C. Alternatively, ketones of formula(2) can be obtained from the selective reduction of enones (6) byhydrogenation in the presence of a catalyst such as 5% platinum/carbon.The reaction is generally conducted in a solvent such as, but notlimited to, tetrahydrofuran, at about room temperature. Enones offormula (6) can also be converted to ketone of formula (2) via atwo-step process wherein the enone is first reduced to a substitutedcycloalkane alcohol, followed by oxidation of the hydroxy functionalityto the corresponding ketone. The reduction and oxidation reactions arewell known in the art.

Ketones of formula (2) when treated with a sodium, potassium, or lithiumbis(trimethylsilyl)amide and a triflating agent provide compounds offormula (3). Examples of suitable triflating agent include, but are notlimited to,1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamideand N-(5-chloro-2-pyridyl)triflimide. The reaction is generallyconducted, for example, at a temperature of about −78° C. to about roomtemperature, in a solvent such as, but not limited to, THF.

Enol triflates of formula (3) can be converted to amides of formula (4)when treated with amines of formula R³R⁴NH, in the presence of carbonmonoxide, a base and a palladium catalyst such as, but not limited to,[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II).Alternatively, enol triflates of formula (3) can be transformed toamides of formula (4) by treating with R³R⁴NH in the presence of carbonmonoxide atmosphere, a base, a palladium catalyst such as palladium (II)acetate, and a ligand such as, but not limited to,2-dicyclohexylphosphino-2′-(N,N-dimethylamino)biphenyl,1,3-bis(diphenylphosphino)propane, triphenylphosphine, or2-dicyclohexylphosphine-2′-(N,N-dimethylamino)biphenyl). Examples ofbases that are suitable for the conversion include, but are not limitedto, an organic base such as triethylamine, or an inorganic base such ascesium carbonate. The reaction is generally conducted at a temperatureof about room temperature to about 100° C., in a solvent such as, butnot limited to, DMF, THF, dioxane, or mixtures thereof. Alternatively,compounds of formula (4) can be synthesized from esters of formula (5)wherein R¹⁰¹ is alkyl (prepared in turn from enol triflates of formula(3) by treatment with carbon monoxide and alcohols of formula R¹⁰¹OH, inthe presence of a base, a palladium catalyst and a ligand). The esters(5) can be transformed to compounds of formula (4) usingtrimethylaluminum and amines of formula R³R⁴NH in a solvent such as, butnot limited to, toluene or dichloromethane. Single enantiomers offormula (4) can be separated by chiral HPLC using a chiral column suchas, but not limited to, Chiralcel OD or Chiralcel AS column (chiralTechnologies Inc., West Chester, Pa.).

Compounds of formula (1) wherein R² is —OH, —O(alkyl), —O(haloalkyl),fluorine or chlorine, can be synthesized using general procedures suchas those depicted in Scheme 2.

Ketones (7) can be treated with a base such as n-butyllithium andcompounds of formula R¹R¹⁰³ wherein R¹⁰³ is halides (for example,bromide) or OTf, to provide compounds of formula (8) wherein R¹⁰² ishydrogen. The conversion can be accomplished in a solvent such as, butnot limited to, diethyl ether at a temperature from about −70° C. toabout room temperature. Alkylation of compounds of formula (8) whereinR¹⁰² is hydrogen using conventional alkylating reagent and conditionsknown to one skilled in the art, provides compounds of formula (8)wherein R¹⁰² is alkyl or haloalkyl. For example, compounds (8) whereinR¹⁰² is hydrogen can be treated with a base such as, but not limited to,sodium hydride, and an alkylating reagent such as alkyl halide (forexample, methyl iodide), to provide compounds (8) wherein R¹⁰² is alkyl.The reaction is generally conducted at a temperature of about 25° C., ina solvent such as, but not limited to, THF. Compounds (8) wherein R¹⁰²is hydrogen can be treated either with diethylaminosulfur trifluoride(DAST) or thionyl chloride to provide intermediates (9) or (10)respectively.

Ketones of formula (7) wherein n is 0 is commercially available. Ketones(7) wherein n is 1 and R⁵ is alkyl can be prepared using generalprocedures such as that shown in Scheme 3.

Commercially available 4-hydroxycylohexanone (11) can be protected bytreatment with trialkylsilyl halide such as, but not limited to,tert-butyldimethylsilyl chloride to provide intermediates of formula(12) wherein P¹⁰¹ is trialkylsilyl group. Deprotanation of the ketonesof formula (12) with a base such as, but not limited to, lithiumbis(trimethylsilyl)amide or sodium hydride, followed by treatment withan alkylating reagent such as alkyl halides (for example, methyl iodide)using reaction conditions as described in Scheme 2, provides ketones(13). Protection of the carbonyl functionality followed by thedeprotection of the hydroxy functionality, and oxidation of the hydroxyconverts (13) to (14). The protection, de-protection and oxidationreactions for the conversion of(13) to (14) are well documented in theliterature.

Intermediates of formula (6) wherein R² is haloalkyl or —CN can beprepared using general procedures known to one skilled in the art suchas those shown in Scheme 4.

Compounds of formula (15) wherein R¹⁰³ is halides (for example, bromide)or OTf, can be treated with boronic esters of formula (16) wherein R² ishaloalkyl or —CN, and each R¹⁰⁴ is independently alkyl, to providecompounds of formula (17) using palladium catalyzed coupling reactionconditions known in the literature. For example, the reaction can becarried out in the presence of a palladium catalyst such astetrakis(triphenylphosphine)palladium(0) and a base such as potassium orcesium carbonate, in a solvent such as, but not limited to,1,2-dimethoxyethane, water, or mixtures thereof, and at a temperature ofabout room temperature to about 150° C. Treatment of compounds offormula (17) with dienes of formula (18) wherein P¹⁰² is a hydroxyprotecting group, R¹⁰⁵ is N(alkyl)₂ or O(alkyl), and R¹⁰⁶ is hydrogen oralkyl, in a solvent such as, but not limited to, aromatic hydrocarbonsuch as toluene, at a temperature of about room temperature to about thereflux temperature of the solvent employed, provides cyclohexenes offormula (19). Hydroxy protecting groups are well known in the art.Examples of suitable hydroxy protecting groups include, but are notlimited to, trialkylsilyl group such as, tert-butyldimethyl silyl.Treatment of (19) with acid such as hydrochloric acid in a solvent suchas, but not limited to, tetrahydrofuran, provides compounds of formula(20).

Enones (6) wherein R² is methyl, haloalkyl or —CN can be prepared usinggeneral procedures known to one skilled in the art, such as those shownin Scheme 5.

Hydroboration of compounds of formula (17) using reaction conditionsknown in the art, for example, by treatment with 9-BBN, followed bytreatment with an oxidizing reagent provides hydroxy intermediates offormula (21). Suitable oxidizing reagent includes, but is not limitedto, hydrogen peroxide. Oxidation of (21) provides aldehydes (22). Forexample, (21) can be subjected to Swern oxidative conditions to providealdehydes (22). Aldol condensation of (22) with α, β unsaturated ketones(23) wherein R¹⁰⁷ is hydrogen or alkyl provides enones of formula (24).For example, (22) and (23) can be reacted in the presence of a base suchas, but not limited to, an inorganic base such as potassium hydroxide.

Scheme 6 shows an exemplary synthetic method for the preparation ofketones of formula (2) wherein n is 1 and R⁵ is alkyl.

1,4-conjugate addition of alkyl nucleophiles to enones (25) providessubstituted ketones of formula (26) wherein R⁵ is alkyl. For example,treatment of (25) with an alkyl nucleophile such as, but not limited to,an alkyl Grignard reagent (for example, methyl Grignard), optionally inthe presence of copper(I) iodide, using reaction conditions that areknown in the art, leads to (26).

Compounds of general formula (I) wherein X is S can be made, forexample, as shown in Scheme 7.

For example, treatment of (4) with Lawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)according to procedures described in Chem. Lett. 8, (1955) 713-4 orChem. Lett. 12, (2000) 1398-9, provides compounds of formula (27).

Compounds of formula (I) wherein n is 1 and R⁵ is NH₂, N(H)(alkyl), orN(alkyl)₂ can be prepared utilizing general procedures as outlined inScheme 8.

For example, ketones of formula (28) when treated with a base such assodium, potassium, or lithium bis(trimethylsilyl)amide andtriisopropylsilyl chloride provide triisopropylsilyl (TIPS) enol ethers(29). Treatment of triisopropylsilyl (TIPS) enol ethers (29) withiodosyl benzene in the presence of trimethylsilyl azide produces β-azidoadduct (30). Ketones of formula (31) can be derived from treatment of(30) with acids such as hydrochloric acid. Manipulation of intermediates(31) using reaction conditions as described in Schemes 1 and 5, followedby reduction of the azide with lithium aluminum hydride give the amine(32). The amino group in compounds of formula (32) can be mono ordi-alkylated using reaction conditions known to one skilled in the art.

It will be appreciated that the synthetic schemes and specific examplesas illustrated in the Examples section are illustrative and are not tobe read as limiting the scope of the invention as it is defined in theappended claims. All alternatives, modifications, and equivalents of thesynthetic methods and specific examples are included within the scope ofthe claims.

Optimum reaction conditions and reaction times for each individual stepmay vary depending on the particular reactants employed and substituentspresent in the reactants used. Unless otherwise specified, solvents,temperatures and other reaction conditions may be readily selected byone of ordinary skill in the art. Specific procedures are provided inthe Synthetic Examples section. Reactions may be worked up in theconventional manner, e.g. by eliminating the solvent from the residueand further purified according to methodologies generally known in theart such as, but not limited to, crystallization, distillation,extraction, trituration and chromatography. Unless otherwise described,the starting materials and reagents are either commercially available ormay be prepared by one skilled in the art from commercially availablematerials using methods described in the chemical literature.

Routine experimentations, including appropriate manipulation of thereaction conditions, reagents and sequence of the synthetic route,protection of any chemical functionality that may not be compatible withthe reaction conditions, and deprotection at a suitable point in thereaction sequence of the method are included in the scope of theinvention. Suitable protecting groups and the methods for protecting anddeprotecting different substituents using such suitable protectinggroups are well known to those skilled in the art; examples of which maybe found in T. Greene and P. Wuts, Protecting Groups in ChemicalSynthesis (3^(rd) ed.), John Wiley & Sons, NY (1999), which isincorporated herein by reference in its entirety. Synthesis of thecompounds of the invention may be accomplished by methods analogous tothose described in the synthetic schemes described hereinabove and inspecific examples.

Starting materials, if not commercially available, may be prepared byprocedures selected from standard organic chemical techniques,techniques that are analogous to the synthesis of known, structurallysimilar compounds, or techniques that are analogous to the abovedescribed schemes or the procedures described in the synthetic examplessection.

When an optically active form of a compound of the invention isrequired, it may be obtained by carrying out one of the proceduresdescribed herein using an optically active starting material (prepared,for example, by asymmetric induction of a suitable reaction step), or byresolution of a mixture of the stereoisomers of the compound orintermediates using a standard procedure (such as chromatographicseparation, recrystallization or enzymatic resolution).

Similarly, when a pure geometric isomer of a compound of the inventionis required, it may be obtained by carrying out one of the aboveprocedures using a pure geometric isomer as a starting material, or byresolution of a mixture of the geometric isomers of the compound orintermediates using a standard procedure such as chromatographicseparation.

Following Examples may be used for illustrative purposes and should notbe deemed to narrow the scope of the invention.

g) EXAMPLES Example 14-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamideExample 1A 8-(3-chloropyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a −60° C. solution of n-butyl lithium (23 mL, 2.5M in hexane, 58.2mmol) in diethyl ether (40 mL) was added a solution of2-bromo-3-chloropyridine (Alfa, 8.0 g, 41.6 mmol) in diethyl ether (60mL) over 15 minutes. The reaction mixture was stirred for 40 minutesfollowed by a slow addition (about 15 minutes) of a solution of1,4-dioxaspiro[4.5]decan-8-one (Aldrich, 8.44 g, 54.0 mmol) in diethylether (100 mL), and stirred until reaction mixture warmed up to ambienttemperature (about 3 hours). The mixture was quenched with saturatedNH₄Cl, diluted with ethyl acetate and washed with water. The organiclayer was separated, concentrated and the residue crystallized fromethyl acetate-hexanes to obtain 5.5 g of the title compound. Two morecrystallizations of the mother liquors yielded 1.61 g more material.Total yield 7.13 g (64%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.59 (d,J=12.69 Hz, 2H), 1.80 (d, J=12.69 Hz, 2H), 1.94 (td, J=12.69, 4.36 Hz,2H), 2.30-2.41 (m, 2H), 3.88 (s, 4H), 5.36 (s, 1H), 7.36 (dd, J=7.93,4.76 Hz, 1H), 7.88 (dd, J=7.93, 1.59 Hz, 1H), 8.48 (dd, J=4.76, 1.59 Hz,1H). MS (DCI) m/z 270.10 (M+H)⁺.

Example 1B 3-chloro-2-(8-fluoro-1,4-dioxaspiro[4.5]dec-8-yl)pyridine

To a −78° C. solution of the product of Example 1A (7.13 g, 26.4 mmol)in CH₂Cl₂ (120 mL) was added diethylaminosulfur trifluoride (DAST, 6.0g, 4.89 mL, 37.0 mmol). The reaction mixture was allowed to warm toambient temperature, quenched with water, diluted with ethyl acetate,and washed with water. The organic layer was separated and concentrated.The resulting residue was chromatographed on silica gel, eluting with0%-30% ethyl acetate-hexane to obtain the title compound (3.0 g, 42%).¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.69-1.77 (m, 2H), 1.86 (td, J=12.89,4.75 Hz, 2H), 2.15-2.40 (m, 4H), 3.91 (s, 4H), 7.44 (ddd, J=8.14, 4.75,0.68 Hz, 1H), 7.96 (dd, J=7.97, 1.53 Hz, 1H), 8.52 (dt, J=4.75, 1.19 Hz,1H). MS (DCI) m/z 272.05 (M+H)⁺.

Example 1C 4-(3-chloropyridin-2-yl)-4-fluorocyclohexanone

To a solution of the product of Example 1B (3.0 g, 11.04 mmol) indioxane (50 mL) was added 3M HCl (50 mL). The reaction mixture wasstirred overnight at ambient temperature, quenched with 3M NaOH (50 mL)and extracted with ethyl acetate. The organic layer was separated andconcentrated. The resulting residue was chromatographed on silica geleluting with 0%-30% ethyl acetate-hexane to obtain 95% pure desiredproduct (2.6 g, 103%) as a white solid. ¹H NMR (300 MHz, DMSO-d₆) δ PPM2.29-2.37 (M, 2H), 2.54-2.75 (M, 6H), 7.48 (DDD, J=8.14, 4.75, 1.02 HZ,1H), 8.01 (DD, J=8.14, 1.70 HZ, 1H), 8.54 (D, J=4.75 HZ, 1H). MS (DCI)M/Z 228.01 (M+H)⁺.

Example 1D 4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-en-1-yltrifluoromethanesulfonate

To a −78° C. solution of the product of Example 1C (3.0 g, 13.18 mmol)and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(5.18 g, 14.50 mmol) in tetrahydrofuran (100 mL) was added lithiumbis(trimethylsilyl)amide (1M in tetrahydrofuran, 14.5 mL, 14.50 mmol)over 5 minutes. The reaction mixture was stirred for 1.5 hours at −78°C. and then another 1.5 hours at ambient temperature, quenched with 1NNaOH (200 mL), and extracted with ethyl acetate. The organic phase waswashed with water. Organic layer was separated and concentrated. Theresidue was chromatographed on silica gel eluting with 0%-30% ethylacetate-hexane to obtain the title compound (4.1 g, 86%) as 92-94% pureviscous oil. ¹H NMR (300 MHz, CDCl₃) δ ppm 2.37-2.61 (m, 3H), 2.71-2.84(m, 1H), 2.88-3.01 (m, 1H), 3.06-3.26 (m, 1H), 5.77-5.80 (m, 1H), 7.24(ddd, J=8.14, 4.75, 0.68 Hz, 1H), 7.75 (dd, J=7.97, 1.52 Hz, 1H), 8.44(d, J=4.75 Hz, 1H). MS (DCI) m/z 360.05 (M+H)⁺.

Example 1E4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide

A mixture of the product of Example 1D (1.590 g, 4.42 mmol),4-(trifluoromethyl)aniline (1.424 g, 8.84 mmol), and triethylamine (1.24mL, 8.90 mmol) in dimethylformamide (30 mL) was added to palladium(II)acetate (49.3 mg, 0.220 mmol) and2-dicyclohexylphospino-2′-(dimethylamino)biphenyl (174.7 mg, 0.444 mmol)in a 250 mL pressure bottle under argon. The mixture was pressurizedwith carbon monoxide (60 psi), stirred 14 hours at ambient temperature,treated with ethyl acetate (200 mL), washed with saturated sodiumbicarbonate (200 mL), brine, dried with anhydrous sodium sulfate,filtered, and concentrated. The residue was chromatographed on silicagel, eluting with 0-to-40% ethyl acetate in hexanes, and concentrated toa yellow oil. Repeated chromatography on silica gel, eluting withdichloromethane, then 30% ethyl acetate in dichloromethane afforded1.424g (81% yield) of the title compound as a light yellow solid. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 2.15-2.36 (m, 1H), 2.89-3.01 (m, 1H), 3.08-3.21(m, 1H), 6.75 (s, 1H), 7.49 (ddd, J=8.13, 4.56, 0.79 Hz, 1H), 7.68 (d,J=8.33 Hz, 2H), 7.93 (d, J=8.33 Hz, 2H), 8.03 (dd, J=8.13, 1.39 Hz, 1H),8.56 (d, J=4.76 Hz, 1H), 10.10 (s, 1H). ¹H NMR (300 MHz, CDCl₃) δ ppm2.26-2.47 (m, 1H), 2.55-2.72 (m, 3H), 2.93-3.05 (m, 1H), 3.15-3.33 (m,1H), 6.74 (s, 1H), 7.22-7.27 (m, 1H), 7.58-7.61 (m, 3H), 7.71 (d, J=8.47Hz, 2H), 7.77 (dd, J=8.13, 1.35 Hz, 1H), 8.46 (ddd, J=4.58, 1.52, 0.85Hz, 1H). MS (ESI) m/z 398.95 (M+H)⁺. Calcd for C₁₉H₁₅ClF₄N₂O: C, 57.23;H, 3.79; N, 7.02. Found: C, 57.11; H, 3.49; N, 6.92.

Example 2N-(4-chlorophenyl)-4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting 4-chloroaniline for4-(trifluoromethyl)aniline. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.14-2.36(m, 1H), 2.86-2.99 (m, 1H), 3.12-3.25 (m, 1H), 6.69 (s, 1H), 7.37 (d,J=8.82 Hz, 2H), 7.48 (ddd, J=8.14, 4.57, 0.85 Hz, 1H), 7.73 (d, J=8.82Hz, 2H), 8.02 (dd, J=8.14, 1.36 Hz, 1H), 8.55 (d, J=4.40 Hz, 1H), 9.88(s, 1H). ¹H NMR (300 MHz, MeOH-d₄) δ ppm 2.27-2.64 (m, 4H), 2.86-2.99(m, 1H), 3.13-3.27 (m, 1H), 6.70 (s, 1H), 7.31 (d, J=9.15 Hz, 2H), 7.36(ddd, J=8.14, 4.75, 0.68 Hz, 1H), 7.61 (d, J=9.16 Hz, 2H), 7.89 (d,J=8.14 Hz, 1H), 8.47 (d, J=4.74 Hz, 1H). MS (ESI) m/z 364.94 (M+H)⁺.Calcd for C₁₈H₁₅Cl₂FN₂O: C, 59.19; H, 4.14; N, 7.67. Found: C, 58.92; H,4.01; N, 7.51.

Example 34-(3-chloropyridin-2-yl)-4-fluoro-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting 4-(trifluoromethylsulfonyl)anilinefor 4-(trifluoromethyl)aniline. ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.15-2.36 (m, 1H), 2.90-3.03 (m, 1H), 3.11-3.22 (m, 1H), 6.82 (s, 1H),7.49 (dd, J=8.13, 4.56 Hz, 1H), 8.03 (dd, J=8.14, 1.39 Hz, 1H), 8.07 (d,J=9.12 Hz, 2H), 8.15 (d, J=9.52 Hz, 2H), 8.56 (d, J=4.36 Hz, 1H), 10.50(s, 1H). ¹H NMR (300 MHz, CDCl₃) δ ppm 2.25-2.46 (m, 1H), 2.56-2.73 (m,3H), 2.94-3.08 (m, 1H), 3.17-3.27 (m, 1H), 6.78 (s, 1H), 7.23-7.28 (m,1H), 7.76-7.79 (m, 2H), 7.89 (d, J=9.12 Hz, 2H), 8.01 (d, J=8.72 Hz,2H), 8.46 (d, J=4.36 Hz, 1H). MS (ESI) m/z 462.95 (M+H)⁺. Calcd forC₁₉H₁₅ClF₄N₂O₃S: C, 49.30; H, 3.27; N, 6.05. Found: C, 49.29; H, 3.07;N, 5.68.

Example 4N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting 4-tert-butylaniline for4-(trifluoromethyl)aniline. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.26 (s,9H), 2.15-2.36 (m, 1H), 2.85-2.99 (m, 1H), 3.04-3.24 (m, 1H), 6.66 (s,1H), 7.32 (d, J=8.81 Hz, 2H), 7.48 (ddd, J=8.14, 4.57, 0.85 Hz, 1H),7.59 (d, J=8.82 Hz, 2H), 8.02 (dd, J=8.14, 1.70 Hz, 1H), 8.55 (d, J=4.41Hz, 1H), 9.66 (s, 1H). ¹H NMR (300 MHz, CDCl₃) δ ppm 1.31 (s, 9H),2.28-2.49 (m, 1H), 2.52-2.72 (m, 3H), 2.90-3.04 (m, 1H), 3.11-3.31 (m,1H), 6.69 (s, 1H), 7.27 (dd, J=7.80, 4.74 Hz, 1H), 7.36 (d, J=8.81 Hz,2H), 7.46 (s, 1H), 7.48 (d, J=8.82 Hz, 2H), 7.79 (dd, J=8.14, 1.36 Hz,1H), 8.49 (d, J=4.41 Hz, 1H). MS (ESI) m/z 387.08 (M+H)⁺. Calcd forC₂₂H₂₄ClFN₂O: C, 68.30; H, 6.25; N, 7.24. Found: C, 67.92; H, 6.25; N,7.07.

Example 54-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethoxy)phenyl]cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting 4-(trifluoromethoxy)aniline for4-(trifluoromethyl)aniline. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.14-2.37(m, 1H), 2.86-3.00 (m, 1H), 3.06-3.26 (m, 1H), 6.70 (s, 1H), 7.32 (d,J=9.15 Hz, 2H), 7.48 (ddd, J=8.14, 4.75, 0.68 Hz, 1H), 7.80 (d, J=9.15Hz, 2H), 8.02 (dd, J=8.14, 1.70 Hz, 1H), 8.55 (d, J=4.75 Hz, 1H), 9.94(s, 1H). ¹H NMR (300 MHz, CD₃OD) δ ppm 2.27-2.66 (m, 4H), 2.86-2.99 (m,1H), 6.72 (s, 1H), 7.23 (d, J=9.12 Hz, 2H), 7.36 (ddd, J=8.13, 4.56,0.80 Hz, 1H), 7.71 (d, J=9.12 Hz, 2H), 7.89 (dd, J=8.14, 1.39 Hz, 1H),8.48 (d, J=4.76 Hz, 1H). MS (ESI) m/z 414.98 (M+H)⁺. Calcd forC₁₉H₁₅ClF₄N₂O₂: C, 55.02; H, 3.65; N, 6.75. Found: C, 54.79; H, 3.52; N,6.74.

Example 64-(3-chloropyridin-2-yl)-N-[4-(1-cyano-1-methylethyl)phenyl]-4-fluorocyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting2-(4-aminophenyl)-2-methylpropanenitrile for 4-(trifluoromethyl)aniline.¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.67 (s, 6H), 2.14-2.37 (m, 1H),2.86-3.00 (m, 1H), 3.06-3.25 (m, 1H), 6.70 (s, 1H), 7.45 (d, J=8.82 Hz,2H), 7.49 (ddd, J=8.14, 4.58, 0.85 Hz, 1H), 7.74 (d, J=9.15 Hz, 2H),8.02 (dd, J=8.14, 1.36 Hz, 1H), 8.56 (d, J=4.41 Hz, 1H), 9.84 (s, 1H).¹H NMR (300 MHz, CDCl₃) δ ppm 1.72 (s, 6H), 2.25-2.47 (m, 1H), 2.54-2.72(m, 3H), 2.91-3.05 (m, 1H), 3.12-3.32 (m, 1H), 6.72 (s, 1H), 7.24 (ddd,J=8.13, 4.41, 0.68 Hz, 1H), 7.44 (d, J=8.81 Hz, 2H), 7.49 (s, 1H), 7.59(d, J=8.81 Hz, 2H), 7.76 (dd, J=8.14, 1.02 Hz, 1H), 8.46 (d, J=4.41 Hz,1H). MS (ESI) m/z 398.05 (M+H)⁺.

Example 7N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-4-methoxycyclohex-1-ene-1-carboxamideExample 7A 3-chloro-2-(8-methoxy-1,4-dioxaspiro[4.5]dec-8-yl)pyridine

To a solution of the product of Example 1A (2.16 g, 8.00 mmol) intetrahydrofuran (70 mL) was added 60% sodium hydride (0.96 g, 24.0 mmol)in portions, followed by addition of methyl iodide (1.6 mL, 25.6 mmol).The reaction mixture was stirred at ambient temperature for 5 hours,quenched with saturated ammonium chloride (300 mL), extracted with ethylacetate (300 mL), washed with water (300 mL), brine, dried withanhydrous sodium sulfate, filtered, and concentrated to a yellow oil.The residue was chromatographed on silica gel, eluting with 0-to-30%ethyl acetate in hexanes to provide 2.147 g (94% yield) of the titlecompound as a colorless oil. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.59 (d,J=12.55 Hz, 2H), 1.80 (td, J=12.88, 3.73 Hz, 2H), 2.04 (td, J=13.57,3.73 Hz, 2H), 2.23-2.32 (m, 2H), 2.92 (s, 3H), 3.87 (s, 4H), 7.37 (dd,J=7.97, 4.58 Hz, 1H), 7.88 (dd, J=7.97, 1.53 Hz, 1H), 8.51 (dd, J=4.58,1.53 Hz, 1H). MS (DCI) m/z 284.13 (M+H)⁺.

Example 7B 4-(3-chloropyridin-2-yl)-4-methoxycyclohexanone

To a solution of the product of Example 7A (2.147 g, 7.57 mmol) indioxane (40 mL) was added 3N hydrochloric acid (25 mL). The reactionmixture was stirred at ambient temperature for 3 hours, quenched with 3Nsodium hydroxide (35 mL), followed by addition of water (200 mL),extracted twice with ethyl acetate (200 mL), washed with water (200 mL)and brine, dried with anhydrous sodium sulfate, filtered andconcentrated to a yellow oil. The residue was chromatographed on silicagel, eluting with 0-to-30% ethyl acetate in hexane to provide 1.698 g(94% yield) of the title compound as a white solid. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 2.17-2.31 (m, 4H), 2.54-2.65 (m, 4H), 3.01 (s, 3H), 7.42(dd, J=7.97, 4.58 Hz, 1H), 7.94 (dd, J=8.14, 1.36 Hz, 1H), 8.54 (dd,J=4.58, 1.53 Hz, 1H). MS (DCI) m/z 240.05 (M+H)⁺.

Example 7C 4-(3-chloropyridin-2-yl)-4-methoxycyclohex-1-en-1-yltrifluoromethanesulfonate

A solution of the product of Example 7B (1.648 g, 6.88 mmol) and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(2.59 g, 7.25 mmol) in tetrahydrofuran (35 mL) was chilled to −75° C.,followed by drop-wise addition of lithium bis(trimethylsilyl)amide (1.0Min tetrahydrofuran, 8.4 mL, 8.4 mmol) over 10 minutes. The resultingmixture was stirred at −75° C. for 50 minutes, then warmed to ambienttemperature by removing the cold bath, and stirred for 2 hours. Themixture was then treated with 1N sodium hydroxide (200 mL) and extractedtwice with 1:1 ethyl acetate:hexanes (200 mL). The combined organiclayers were washed with 1N sodium hydroxide (200 mL), water (200 mL),and brine, dried with anhydrous sodium sulfate, filtered, andconcentrated to an orange oil. The residue was chromatographed on silicagel, eluting with 0-to-25% ethyl acetate in hexanes to provide 2.089 g(82% yield) of the title compound as a colorless oil. ¹H NMR (300 MHz,CDCl₃) δ ppm 2.20-2.29 (m, 1H), 2.42-2.63 (m, 3H), 2.81-2.98 (m, 2H),3.07 (s, 3H), 5.75 (t, J=4.24 Hz, 1H), 7.20 (dd, J=7.97, 4.58 Hz, 1H),7.71 (dd, J=7.97, 1.53 Hz, 1H), 8.45 (dd, J=4.58, 1.53 Hz, 1H). MS (DCI)m/z 372.07 (M+H)⁺.

Example 7DN-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-4-methoxycyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting 4-tert-butylaniline for4-(trifluoromethyl)aniline, and substituting the product of Example 7Cfor the product of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 1.26 (s,9H), 2.20-2.42 (m, 4H), 2.85 (s, 2H), 2.95 (s, 3H), 6.65 (t, J=3.77 Hz,1H), 7.30 (d, J=8.72 Hz, 2H), 7.41 (dd, J=8.13, 4.56 Hz, 1H), 7.57 (d,J=8.72 Hz, 2H), 7.94 (dd, J=8.13, 1.39 Hz, 1H), 8.53 (dd, J=4.76, 1.58Hz, 1H), 9.54 (s, 1H). MS (ESI) m/z 399.12 (M+H)⁺. Calcd forC₂₃H₂₇ClN₂O₂: C, 69.25; H, 6.82; N, 7.02. Found: C, 69.34; H, 6.79; N,7.24.

Example 84-(3-chloropyridin-2-yl)-4-methoxy-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting 4-(trifluoromethylsulfonyl)anilinefor 4-(trifluoromethyl)aniline, and substituting the product of Example7C for the product of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm2.21-2.44 (m, 4H), 2.90 (s, 2H), 2.96 (s, 3H), 6.81 (t, J=3.90 Hz, 1H),7.42 (dd, J=8.14, 4.41 Hz, 1H), 7.95 (dd, J=7.97, 1.52 Hz, 1H), 8.06 (d,J=9.16 Hz, 2H), 8.14 (d, J=9.16 Hz, 2H), 8.53 (dd, J=4.75, 1.35 Hz, 1H),10.39 (s, 1H). MS (ESI) m/z 475.02 (M+H)⁺. Calcd forC₂₀H₁₈ClF₃N₂O₄S.0.16 TFA: C, 49.49; H, 3.71; N, 5.68. Found: C, 49.57;H, 3.57; N, 5.42.

Example 94-(3-chloropyridin-2-yl)-4-methoxy-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 7C for theproduct of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.21-2.43 (m,4H), 2.87 (s, 2H), 2.96 (s, 3H), 6.73 (t, J=3.77 Hz, 1H), 7.41 (dd,J=8.13, 4.56 Hz, 1H), 7.66 (d, J=9.12 Hz, 2H), 7.92 (d, J=9.52 Hz, 2H),7.95 (dd, J=7.93, 1.58 Hz, 1H), 8.54 (dd, J=4.56, 1.39 Hz, 1H), 9.99 (s,1H). MS (ESI) m/z 411.02 (M+H)⁺. Calcd for C₂₀H₁₈ClF₃N₂O₂. 0.13 TFA: C,57.17; H, 4.29; N, 6.58. Found: C, 57.19; H, 3.84; N, 6.44.

Example 104-fluoro-4-(3-methylpyridin-2-yl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamideExample 10A 8-(3-methylpyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol

The title compound was prepared using the procedure as described inExample 1A, except for substituting 3-methyl-2-bromopyridine for3-chloro-2-bromopyridine.

¹H NMR (300 MHz, DMSO-d₆) δ 8.32 (dd, J 1.5 and 4.5 Hz, 1H), 7.52 (dd, J1.5 and 7.5 Hz, 1H), 7.16 (dd, J 4.5 and 7.5 Hz, 1H), 5.21 (s, 1H), 3.85(s, 4H), 2.53 (s, 3H), 2.20 (m, 2H), 1.92 (m, 2H), 1.70 (m, 2H), 1.58(m, 2H). MS (DCI/NH₃) m/e 250 (M+H)⁺.

Example 10B 2-(8-fluoro-1,4-dioxaspiro[4.5]dec-8-yl)-3-methylpyridine

The title compound was prepared using the procedure as described inExample 1B, except for substituting the product of Example 10A for theproduct of Example 1A. ¹H NMR (300 MHz, DMSO-d₆) δ 8.37 (d, J=4.5 Hz,1H), 7.60 (d, J=7.5 Hz, 1H), 7.23 (dd, J 4.5 and 7.5 Hz, 1H), 3.90 (s,4H), 2.45-1.62 (m, I 1H). MS (DCI/NH₃) m/e 252 (M+H)⁺.

Example 10C 4-fluoro-4-(3-methylpyridin-2-yl)cyclohexanone

The title compound was prepared using the procedure as described inExample 1C, except for substituting the product of Example 10B for theproduct of Example 1B. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.37 (d, J=4.4Hz, 1H) 7.66 (d, J=6.8 Hz, 1H) 7.29 (dd, J=6.8, 4.4 Hz, 1H), 2.54-2.93(m, 4H), 2.51 (s, 3H), 2.18-2.46 (m, 4H). MS (DCI) m/e 208 (M+H)⁺.

Example 10D 4-fluoro-4-(3-methylpyridin-2-yl)cyclohex-1-en-1-yltrifluoromethanesulfonate

The title compound was prepared using the procedure as described inExample 1D, except for substituting the product of Example 10C for theproduct of Example 1C. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.37 (d, J=5.2Hz, 1H) 7.66 (d, J=7.1 Hz, 1H) 7.30 (dd, J=7.1, 5.2 Hz, 1H) 5.86-6.01(m, 1H) 2.99-3.29 (m, 2H) 2.54-2.86 (m, 2H) 2.47 (d, J=5.6 Hz, 3H)2.27-2.44 (m, 2H). MS (DCI) m/e 340(M+H)⁺.

Example 10E4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 10D for theproduct of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.09 (s, 1H),8.39 (d, J=4.8 Hz, 1H), 7.93 (d 2H), 7.68 (m, 3H), 7.30 (dd, J=7.80, 4.8Hz, 1H), 6.72-6.79 (m, 1H), 3.06-3.25 (m, 2H), 2.66-2.86 (m, 2H), 2.51(s, 3H), 2.04-2.38 (m, 2H). MS (ESI) m/e 379(M+H)⁺. Calc. forC₂₀H₁₈F₄N₂O.0.2H₂O: C, 62.89; H, 4.86; N, 7.33. Found C, 62.81; H, 4.71;N, 7.38.

Example 114-fluoro-4-(3-methylpyridin-2-yl)-N-[4-(trifluoromethoxy)phenyl]cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 10D for theproduct of Example 1D and substituting 4-trifluoromethoxyaniline for4-trifluoromethylaniline. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.93 (s, 1H),8.39 (m, 1H) 7.77-7.85 (m, 2H), 7.67 (m, 1H), 7.22-7.36 (m, 3H), 6.71(br s, 1H), 3.26-3.36 (m, 2H), 3.00-3.24 (m, 1H), 2.62-2.87 (m, 1H),2.51 (s, 3H), 2.01-2.38 (m, 2H). MS (ESI) m/e 395(M+H)⁺. Calc. forC₂₀H₁₈F₄N₂O₂: C, 60.91; H, 4.60; N, 7.10. Found C, 60.75; H, 4.45; N,7.03.

Example 124-fluoro-4-(3-methylpyridin-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 10D forExample 1D and substituting 4-trifluoromethylsulfonylaniline for4-trifluoromethylaniline. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.49 (s, 1H)8.11-8.23 (m, 2H), 8.01-8.11 (m, 2H), 7.67 (d, J=7.1 Hz, 1H), 7.30 (m,1H), 6.83 (br s, 1H), 3.26-3.36 (m, 2H), 3.04-3.26 (m, 1H), 2.61-2.93(m, 1H), 2.50 (s, 3H), 1.86-2.41 (m, 2H). MS (ESI) m/e 443(M+H)⁺. Calc.for C₂₀H₁₈F₄N₂O₃S: C, 54.30; H, 4.10; N, 6.33. Found C 54.07; H, 3.97;N, 6.23.

Example 13N-(4-chlorophenyl)-4-fluoro-4-(3-methylpyridin-2-yl)cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 10D for theproduct of Example 1D and substituting 4-chloroaniline for4-trifluoromethylaniline. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.87 (s, 1H)8.39 (d, J=4.4 Hz, 1H), 7.71-7.83 (m, 2H), 7.66 (d, J=6.7 Hz, 1H),7.18-7.46 (m, 3H), 6.70 (s, 1H), 3.26-3.36 (m, 2H), 3.02-3.23 (m, 1H),2.61-2.88 (m, 1H), 2.51 (s, 3H) 2.02-2.37 (m, 2H). Calc. forC₁₉H₁₈ClFN₂O.0.1H₂O: C, 65.84; H, 5.29; N, 8.08. Found C, 65.70; H,5.02; N, 7.98.

Example 14N-(4-tert-butylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl)cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 10D for theproduct of Example 1D and substituting 4-tert-butylaniline for4-trifluoromethylaniline. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.64 (s, 1H),8.39 (d, J=4.4 Hz, 1H) 7.49-7.78 (m, 3H), 7.16-7.41 (m, 3H), 6.67 (br s,1H), 3.22-3.30 (m, 1H), 2.94-3.22 (m, 1H), 2.64-2.86 (m, 1H), 2.51 (s,3H), 1.96-2.37 (m, 2H), 1.27 (s, 9H). MS (ESI) m/e 367 (M+H)⁺. Calc. forC₂₃H₂₇FN₂O: C, 75.38; H, 7.43; N, 7.64. Found C, 75.17; H, 7.33; N,7.58.

Example 154-fluoro-4-(3-fluoropyridin-2-yl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamideExample 15A 8-(3-fluoropyridin-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol

The title compound was prepared using the procedure as described inExample 1A, except for substituting 3-fluoro-2-bromopyridine for3-chloro-2-bromopyridine. ¹H NMR (300 MHz, DMSO-d₆) δ 8.36 (m, 1H), 7.66(m, 1H), 7.41 (m, 1H), 5.21 (s, 1H), 3.85 (s, 4H), 2.20 (m, 2H), 1.92(m, 2H), 1.74 (m, 2H), 1.59 (m, 2H). MS (DCI/NH₃) m/e 254 (M+H)⁺.

Example 15B 3-fluoro-2-(8-fluoro-1,4-dioxaspiro[4.5]dec-8-yl)pyridine

The title compound was prepared using the procedure as described inExample 1B, except for substituting the product of Example 15A for theproduct of Example 1A. ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (m, 1H), 7.78(m, 1H), 7.50 (m, 1H), 3.90 (s, 4H), 2.38-1.70 (m, 8H). MS (DCI/NH₃) m/e252 (M+H)⁺.

Example 15C 4-fluoro-4-(3-fluoropyridin-2-yl)cyclohexanone

The title compound was prepared using the procedure as described inExample 1C, except for substituting the product of Example 15B for theproduct of Example 1B. ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (m, 1H), 7.80(m, 1H), 7.56 (m, 1H), 2.80-2.22 (m, 8H). MS (DCI/NH₃) m/e 212 (M+H)⁺.

Example 15D 4-fluoro-4-(3-fluoropyridin-2-yl)cyclohex-1-en-1-yltrifluoromethanesulfonate

The title compound was prepared using the procedure as described inExample 1D, except for substituting the product of Example 15C for theproduct of Example 1C. ¹H NMR (300 MHz, DMSO-d₆) δ 8.41 (m, 1H), 7.81(m, 1H), 7.58 (m, 1H), 5.95 (m, 1H), 3.20-2.20 (m, 6H). MS (DCI/NH₃) m/e344 (M+H)⁺.

Example 15E4-fluoro-4-(3-fluoropyridin-2-yl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 15D for theproduct of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.10 (s, 1H),8.45 (d, J=4.4 Hz, 1H), 7.78-8.00 (m, 3H), 7.68 (d, J=8.5 Hz, 2H),7.50-7.62 (m, 1H), 6.65-6.85 (m, 1H), 3.23-3.32 (m, 1H), 3.03-3.22 (m,1H), 2.69-2.96 (m, 1H), 2.51-2.60 (m, 1H), 2.38-2.47 (m, 1H), 2.04-2.31(m, 1H). MS (ESI) m/e 383 (M+H)⁺. Calc. for C₁₉H₁₅F₅N₂O: C, 59.69; H,3.95; N, 7.33. Found C, 59.73; H, 3.83; N, 7.29.

Example 16N-(4-tert-butylphenyl)-4-fluoro-4-(3-fluoropyridin-2-yl)cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 15D forExample 1D and substituting 4-tert-butylaniline for4-trifluoromethylaniline. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.66 (s, 1H)8.45 (d, J=4.4 Hz, 1H) 7.83 (dd, J=11.9, 7.1 Hz, 1H) 7.48-7.68 (m, 3H)7.23-7.39 (m, 2H) 6.67 (br s, 1H) 3.25-3.43 (m, 2H) 2.98-3.21 (m, 1H)2.67-2.94 (m, 1H) 2.35-2.46 (m, 1H) 1.98-2.33 (m, 1H) 1.26 (s, 9H). MS(ESI) m/e (M+H)⁺. Calc. for C₂₂H₂₄F₂N₂O: C, 71.33; H, 6.53; N, 7.56.Found C, 71.19; H, 6.59; N, 7.54.

Example 174-fluoro-4-(3-fluoropyridin-2-yl)-N-[5-(trifluoromethyl)pyridin-2-yl]cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting Example the product of 15D for theproduct of Example 1D and substituting 2-amino-5-trifluoromethylpyridinefor 4-trifluoromethylaniline. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.65 (brs, 1H), 8.73 (m, 1H), 8.44 (m, 1H), 8.28 (m, 1H), 8.18 (m, 1H), 7.82 (m,1H), 7.56 (m, 1H) 6.90 (m, 1H) 3.22-3.42 (m, 1H) 3.01-3.22 (m, 1H)2.67-2.95 (m, 1H) 2.51-2.61 (m, 1H) 2.33-2.46 (m, 1H) 2.02-2.31 (m, 1H).MS (ESI) m/e 384 (M+H)⁺. Calc. for C₁₈H₁₄F₅N₃O: C, 56.40; H, 3.68; N,10.96. Found C, 56.41; H, 3.45; N, 10.74.

Example 184-fluoro-4-(3-fluoropyridin-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 15D for theproduct of Example 1D and substituting 4-trifluoromethylsulfonylanilinefor 4-trifluoromethylaniline. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.48 (s,1H), 8.45 (d, J=4.4 Hz, 1H), 8.11-8.20 (m, 2H), 8.01-8.11 (m, 2H),7.76-7.89 (m, 1H), 7.50-7.62 (m, 1H), 3.28-3.36 (m, 1H), 3.04-3.26 (m,1H), 2.76-2.98 (m, 1H), 2.51-2.57 (m, 1H), 2.37-2.47 (m, 1H), 2.02-2.34(m, 1H). MS (ESI) m/e 447 (M+H)⁺. Calc. for C₁₉H₁₅F₅N₂O₃S: C, 51.12; H,3.39; N, 6.28. Found C, 50.97; H, 3.32; N, 6.09.

Example 194-fluoro-4-(3-fluoropyridin-2-yl)-N-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 15D for theproduct of Example 1D, and substituting 4-aminophenylsulphurpentafluoride (Aldrich) for 4-trifluoromethylaniline. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 10.18 (s, 1H), 8.45 (d, J=4.4 Hz, 1H), 7.74-8.00 (m, 6H),7.44-7.66 (m, 1H), 6.76 (br s, 1H), 3.23-3.41 (m, 1H), 3.01-3.23 (m,1H), 2.66-2.98 (m, 1H), 2.36-2.60 (m, 2H, under DMSO), 2.00-2.33 (m,1H). MS (ESI) m/e 441 (M+H)⁺. Calc. for C₁₈H₁₅F₇N₂OS: C, 49.09; H, 3.43;N, 6.36. Found C, 49.05; H, 3.35; N, 6.26.

Example 204-fluoro-4-(1,3-thiazol-2-yl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamideExample 20A 8-(1,3-thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol

The title compound was prepared using the procedure as described inExample 1A, except for substituting 2-bromothiazole for3-chloro-2-bromopyridine. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.69 (m, 1H),7.51-7.57 (m, 1H), 3.87 (s, 4H), 2.11 (m, 2H), 1.69-1.95 (m, 4H),1.52-1.70 (m, 2H). MS (DCI) m/e 242 (M+H)⁺.

Example 20B 2-(8-fluoro-1,4-dioxaspiro[4.5]dec-8-yl)-1,3-thiazole

The title compound was prepared using the procedure as described inExample 1B, except for substituting the product of Example 20A for theproduct of Example 1A. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.67-7.99 (m,2H), 3.97 (s, 4H), 2.23-2.40 (m, 1H), 2.06-2.25 (m, 3H), 1.64-1.92 (m,4H). MS (DCI) m/e 244 (M+H)⁺.

Example 20C 4-fluoro-4-(1,3-thiazol-2-yl)cyclohexanone

The title compound was prepared using the procedure as described inExample 1C, except for substituting the product of Example 20B for theproduct of Example 1B. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.82-7.95 (m,2H), 2.61-2.72 (m, 6H), 2.24-2.42 (m, 2H). MS (DCI) m/e 200 (M+H)⁺.

Example 20D 4-fluoro-4-(1,3-thiazol-2-yl)cyclohex-1-en-1-yltrifluoromethanesulfonate

The title compound was prepared using the procedure as described inExample 1D, except for substituting the product of Example 20C for theproduct of Example 1C. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.85-7.95 (m,2H), 5.90-6.08 (m, 1H), 2.94-3.21 (m, 1H), 2.74-2.95 (m, 1H), 2.58-2.74(m, 1H), 2.17-2.50 (m, 3H). MS (DCI) m/e 332 (M+H)⁺.

Example 20E4-fluoro-4-(1,3-thiazol-2-yl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 20D for theproduct of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.13 (s, 1H),7.81-8.08 (m, 4H), 7.68 (d, J=8.5 Hz, 2H), 6.72 (br s, 1H), 2.97-3.26(m, 1H), 2.69-2.98 (m, 1H), 2.51-2.66 (m, 1H), 2.20-2.41 (m, 2H),1.95-2.21 (m, 1H). MS (ESI) m/e 371(M+H)⁺. Calc. for C₁₇H₁₄F₄N₂OS: C,55.13; H, 3.81; N, 7.56. Found C, 55.16; H, 3.65; N, 7.51.

Example 214-fluoro-4-(1,3-thiazol-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 20D forExample 1D and substituting 4-trifluoromethylsulfonylaniline for4-trifluoromethylaniline. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.52 (s, 1H),7.99-8.23 (m, 4H), 7.82-7.96 (m, 2H), 6.79 (br s, 1H), 2.99-3.26 (m,1H), 2.92 (m, 1H), 2.73 (m, 1H), 2.20-2.43 (m, 2H), 2.04-2.21 (m, 1H).MS (ESI) m/e 435(M+H)⁺. Calc. for C₁₇H₁₄F₄N₂O₃S₂: C, 47.00; H, 3.25; N,6.45. Found C, 47.26; H, 3.25; N, 6.33.

Example 22(4R)—N-(4-chlorophenyl)-4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-ene-1-carboxamide

The title compound was obtained by chiral separation of the product ofExample 2 on a ChiralCel OJ column with 50% isopropanol in hexanes. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 2.14-2.36 (m, 1H), 2.86-2.99 (m, 1H),3.06-3.25 (m, 1H), 6.69 (s, 1H), 7.37 (d, J=9.12 Hz, 2H), 7.48 (dd,J=8.13, 4.56 Hz, 1H), 7.73 (d, J=8.73 Hz, 2H), 8.02 (dd, J=8.13, 1.39Hz, 1H), 8.56 (d, J=3.97 Hz, 1H), 9.88 (s, 1H). MS (ESI) m/z 364.93(M+H)⁺. [α]_(D): +11.6° (c: 1.0, CH₃OH). Calcd for C₁₈H₁₅Cl₂FN₂O: C,59.19; H, 4.14; N, 7.67. Found: C, 58.98; H, 3.90; N, 7.47.

Example 23(4S)—N-(4-chlorophenyl)-4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-ene-1-carboxamide

The title compound was obtained by chiral separation of the product ofExample 2 on a ChiralCel OJ column with 50% isopropanol in hexanes. ¹HNMR (300 MHz, DMSO-d₆) δ ppm 2.13-2.36 (m, 1H), 2.86-2.99 (m, 1H),3.06-3.25 (m, 1H), 6.69 (s, 1H), 7.36 (d, J=9.12 Hz, 2H), 7.49 (ddd,J=8.13, 4.56, 0.79 Hz, 1H), 7.73 (d, J=9.13 Hz, 2H), 8.02 (dd, J=8.13,1.39 Hz, 1H), 8.55 (d, J=4.36 Hz, 1H), 9.88 (s, 1H). MS (ESI) m/z 364.92(M+H)⁺. [α]_(D): −9.7°(c: 1.0, CH₃OH). Calcd for C₁₈H₁₅Cl₂FN₂O: C,59.19; H, 4.14; N, 7.67. Found: C, 58.85; H, 3.91; N, 7.39.

Example 24(4R)-4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide

The title compound was obtained by chiral separation of the product ofExample 1 on a ChiralPak AD-H column with 24% ethanol in supercriticalfluid CO₂— ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.14-2.36 (m, 1H), 2.88-3.01(m, 1H), 3.08-3.20 (m, 1H), 6.75 (s, 1H), 7.48 (ddd, J=8.13, 4.56, 0.79Hz, 1H), 7.68 (d, J=8.33 Hz, 2H), 7.93 (d, J=8.32 Hz, 2H), 8.03 (dd,J=8.33, 1.59 Hz, 1H), 8.56 (d, J=4.36 Hz, 1H), 10.10 (s, 1H). ¹H NMR(300 MHz, CDCl₃) δ ppm 2.25-2.47 (m, 1H), 2.55-2.72 (m, 3H), 2.92-3.05(m, 1H), 3.14-3.33 (m, 1H), 6.74 (s, 1H), 7.23-7.27 (m, 1H), 7.58-7.61(m, 3H), 7.71 (d, J=8.73 Hz, 2H), 7.77 (dd, J=7.93, 1.19 Hz, 1H), 8.46(d, J=4.76 Hz, 1H). MS (ESI) m/z 398.98 (M+H)⁺. [α]_(D): +11.4° (c: 1.0,CH₃OH). Calcd for C₁₉H₁₅ClF₄N₂O: C, 57.23; H, 3.79; N, 7.02; Found: C,57.17; H, 3.63; N, 6.95.

Example 25(4S)-4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide

The title compound was obtained by chiral separation of the product ofExample 1 on a ChiralPak AD-H column with 24% ethanol in supercriticalfluid CO₂— ¹H NMR (300 MHz, DMSO-d₆) δ ppm 2.16-2.36 (m, 1H), 2.94-3.01(m, 1H), 3.08-3.21 (m, 1H), 6.75 (s, 1H), 7.49 (ddd, J=8.14, 4.75, 0.68Hz, 1H), 7.68 (d, J=8.47 Hz, 2H), 7.93 (d, J=8.48 Hz, 2H), 8.03 (dd,J=8.14, 1.69 Hz, 1H), 8.56 (d, J=4.75 Hz, 1H), 10.11 (s, 1H). ¹H NMR(300 MHz, CDCl₃) δ ppm 2.25-2.47 (m, 1H), 2.55-2.72 (m, 3H), 2.92-3.05(m, 1H), 3.14-3.33 (m, 1H), 6.74 (s, 1H), 7.23-7.27 (m, 1H), 7.58-7.61(m, 3H), 7.71 (d, J=8.73 Hz, 2H), 7.77 (dd, J=8.13, 1.39 Hz, 1H), 8.46(d, J=4.37 Hz, 1H). MS (ESI) m/z 398.96 (M+H)⁺. [α]_(D): −10.3° (c: 1.0,CH₃OH). Calcd for C₁₉H₁₅ClF₄N₂O: C, 57.23; H, 3.79; N, 7.02. Found: C,57.21; H, 3.72; N, 6.95.

Example 264-(3-(Dimethylamino)pyridin-2-yl)-4-(trifluoromethyl)-N-(4-(trifluoromethyl)phenyl)cyclohex-1-enecarboxamideExample 26A 3-Chloro-2-(3,3,3-trifluoroprop-1-en-2-yl)pyridine

To a solution of 2-bromo-3-chloropyridine (Matrix, 1.651 g, 8.58 mmol),4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane(Frontier, 2.0 g, 9.01 mmol), and potassium carbonate (4.74 g, 34.3mmol) in degassed 1,2-dimethoxyethane (50 mL) and water (25 mL) wasadded tetrakis(triphenylphosphine)palladium (496 mg, 0.429 mmol). Thereaction mixture was refluxed for 8 hours, cooled to ambienttemperature, diluted with water (200 mL), extracted twice with diethylether (200 mL), washed with brine, dried (Na₂SO₄) and concentrated to ayellow liquid. The residue was purified by silica gel chromatography(AnaLogix® SF25-40G; 50 micron silica; elution with 0-20% ethyl acetatein hexane at 30 mL/min) to provide the title compound (1.530 g, 7.37mmol, 86% yield) as a colorless liquid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm8.61 (dd, J=4.6, 1.4, 1H), 8.10 (dd, J=8.2, 1.4, 1H), 7.53 (dd, J=8.3,4.6, 1H), 6.51-6.46 (m, 1H), 6.13-6.10 (m, 1H); MS (EI) m/e 207 (M)⁺.

Example 26B4-(3-(Dimethylamino)pyridin-2-yl)-4-(trifluoromethyl)cyclohex-2-enone

A solution of Example 26A (418 mg, 2.014 mmol) and(E)-3-(tert-butyldimethylsilyloxy)-N,N-dimethylbuta-1,3-dien-1-amine(Aldrich, 527 mg, 2.316 mmol) in toluene (1.5 mL) was heated in amicrowave at 140° C. for 2 hours, and then chromatographed on silica gel(AnaLogix SF15-24G; 50 micron silica; elution with 0-50% ethyl acetatein hexane at 20 mL/min). Repeated the reaction in a microwave at 120° C.for 2 hours with a solution of Example 26A (422 mg, 2.033 mmol) and(E)-3-(tert-butyldimethylsilyloxy)-N,N-dimethylbuta-1,3-dien-1-amine(693 mg, 3.05 mmol) in toluene (2 mL), and then chromatographed onsilica gel (AnaLogix® SF15-24G; 50 micron silica; elution with 0-50%ethyl acetate in hexane at 20 mL/min). The title compound (165 mg, 0.580mmol) was isolated as an orange solid. A solution of the isolatedintermediate7-(tert-butyldimethylsilyloxy)-5,5-dimethyl-9a-(trifluoromethyl)-5a,8,9,9a-tetrahydro-5H-pyrido[3,2-b]indol-5-iumchloride (395 mg, 0.908 mmol) in tetrahydrofuran (9 mL) was treated with1N hydrochloric acid (3.0 mL, 3.0 mmol). The reaction mixture wasstirred overnight at ambient temperature, quenched with sodiumbicarbonate solution (40 mL), extracted twice with ethyl acetate (40mL), washed with brine, dried (Na₂SO₄), and concentrated to an orangeoil. The residue was purified by silica gel chromatography (AnaLogix® SF10-8G; 50 micron silica; elution with 0-40% ethyl acetate in hexane at15 mL/min) to provide additional title compound (131 mg, 0.461 mmol) asan off-white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.54 (dd, J=4.5, 1.6,1H), 7.75 (dd, J=8.0, 1.7, 1H), 7.74 (dd, J=10.2, 2.1, 1H), 7.35 (dd,J=8.1, 4.5, 1H), 5.90 (d, J=10.2, 1H), 3.54-3.44 (m, 1H), 2.65 (s, 3H),2.45-2.35 (m, 2H), 2.33 (s, 3H), 2.13-1.97 (m, 1H); MS (DCI/NH₃) m/e 285(M+H)⁺.

Example 26C4-(3-(Dimethylamino)pyridin-2-yl)-4-(trifluoromethyl)cyclohexanone

Example 26B (261 mg, 0.918 mmol) was added to a mixture of ethanol (30mL) and tris(triphenylphosphine)rhodium(I) chloride (50 mg, 0.054 mmol)in a Parr shaker. The glass reactor was sealed and flushed with argon,and then it was pressurized with hydrogen (50 psi). The mixture wasshaken at ambient temperature for 24 hours, and concentrated. Theresidue was purified by silica gel chromatography (AnaLogix® SF10-8G; 50micron silica; elution with 0-50% ethyl acetate in hexane at 12 mL/min)to provide the title compound (125 mg, 0.437 mmol, 47.6% yield) as ayellow solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.56 (dd, J=4.4, 1.7, 1H),7.82 (dd, J=8.1, 1.7, 1H), 7.36 (dd, J=8.1, 4.4, 1H), 3.77-3.63 (m, 2H),2.62 (s, 6H), 2.46-2.30 (m, 2H), 2.30-2.11 (m, 4H); MS (DCI/NH₃) m/e 287(M+H)⁺.

Example 26D4-(3-(Dimethylamino)pyridin-2-yl)-4-(trifluoromethyl)cyclohex-1-enyltrifluoromethanesulfonate

A solution of Example 26C (109 mg, 0.381 mmol) andN-phenyltrifluoromethane-sulfonamide (291.1 mg, 0.815 mmol) intetrahydrofuran (5 mL) was chilled to −75° C. with a cooling bath, andtreated with 1M lithium bis(trimethylsilyl)amide (0.92 mL, 0.920 mmol)in tetrahydrofuran. The reaction mixture was stirred at −75° C. for 1hour. The cooling bath was removed and the mixture was allowed to stirovernight at ambient temperature. The reaction mixture was quenched with1N sodium hydroxide (50 mL), extracted twice with ethyl acetate (50 mL),washed with brine, dried (Na₂SO₄) and concentrated. The residue waspurified by silica gel chromatography (AnaLogix® SF10-8G; 50 micronsilica; elution with 0-20% ethyl acetate in hexane at 12 mL/min) toprovide the title compound (134 mg, 320 μmol, 84% yield) as a colorlessoil. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.48 (dd, J=4.4, 1.7, 1H), 7.74 (dd,J=8.1, 1.7, 1H), 7.30 (dd, J=8.0, 4.4, 1H), 5.78 (dd, J=6.8, 1.3, 1H),4.52-4.40 (m, 1H), 3.35-3.24 (m, 1H), 2.69-2.49 (m, 7H), 2.40-2.19 (m,2H), 2.11-1.98 (m, 1H); MS (DCI/NH₃) m/e 419 (M+H)⁺.

Example 26E4-(3-(Dimethylamino)pyridin-2-yl)-4-(trifluoromethyl)-N-(4-(trifluoromethyl)phenyl)cyclohex-1-enecarboxamide

A solution of Example 26D (131 mg, 0.313 mmol),4-(trifluoromethyl)aniline (76 mg, 0.472 mmol), and triethylamine (0.088mL, 0.631 mmol) in dimethylformamide (4 mL) was added to palladium(II)acetate (1.8 mg, 0.008 mmol) and2-dicyclohexylphospino-2′-(dimethylamino)-biphenyl (6.2 mg, 0.016 mmol)in a pressure bottle under argon. The mixture was pressurized withcarbon monoxide (60 psi), and stirred for 16 hours at ambienttemperature, treated with ethyl acetate (50 mL), washed with water (50mL) and brine, dried (Na₂SO₄) and concentrated. The residue was purifiedby silica gel chromatography twice [(1)AnaLogix® SF10-8G; 50 micronsilica; elution with 0-40% ethyl acetate in hexane at 12 mL/min;(2)AnaLogix® SF10-8G; 50 micron silica; elution with 50% dichloromethanein hexane, then 50% ethyl acetate in hexane at 12 mL/min)] to providethe title compound (84 mg, 184 μmol, 58.6% yield) as a light yellowfoam. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.48 (dd, J=4.5, 1.8, 1H), 7.73 (dd,J=8.1, 1.7, 1H), 7.62 (d, J=8.8, 2H), 7.54 (d, J=8.9, 2H), 7.35 (s, 1H),7.29 (dd, J=8.1, 4.5, 1H), 6.88 (d, J=5.4, 1H), 4.42 (dd, J=18.5, 6.1,1H), 3.40-3.28 (m, 1H), 2.75-2.43 (m, 8H), 2.30-2.11 (m, 1H), 2.07-1.95(m, 1H); MS (ESI) m/e 458 (M+H)⁺; Calcd for C₂₂H₂₁F₆N₃O.0.08H₂O.0.20EtOAc: C, 57.47; H, 4.81; N, 8.82. Found: C, 57.47; H, 4.55; N, 8.70.

Example 274-fluoro-4-(1,3-thiazol-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamideExample 27A 8-(thiazol-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol

To a −78° C. solution of n-butyl lithium (10.4 mL, 2.5M in hexane, 26mmol) in diethyl ether (20 mL) was added 2-bromothiazole (3.28 g, 1.8mL, 20 mmol) slowly via syringe. The reaction mixture was stirred for 15minutes, followed by the slow addition of 1,4-dioxaspiro[4.5]decan-8-one(4.22 g, 27 mmol) in diethyl ether (55 mL). The reaction mixture wasallowed to warm to ambient temperature and stirred overnight. Thereaction mixture was quenched with saturated aqueous ammonium chloride(50 mL) and extracted with two portions of ethyl acetate. The combinedorganic layers were concentrated. The residue was chromatographed onsilica gel eluting with 0%-40% ethyl acetate-hexane to obtain the titlecompound (4.53 g, 94%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.69 (d, J=3.2,1H), 7.55 (d, J=3.2, 1H), 3.88 (s, 4H), 2.11 (td, J=4.2, 12.8, 2H),1.93-1.80 (m, 2H), 1.80-1.53 (m, 4H).

MS (DCI) m/z 242 (M+H)⁺.

Example 27B 2-(8-fluoro-1,4-dioxaspiro[4.5]decan-8-yl)thiazole

To a −78° C. solution of the product of Example 27A (4.53 g, 17.77 mmol)in methylene chloride (50 mL) was added diethylaminosulfur trifluoride(DAST) (4.18 g, 3.97 mL, 30.0 mmol). The reaction mixture was stirred at−78° C. for four hours, then allowed to warm to ambient temperature, andstirred overnight. The reaction mixture was then cooled to 0° C.,quenched with saturated aqueous sodium bicarbonate, and extracted withmethylene chloride. The organic layer was separated and concentrated.The resulting residue was chromatographed on silica gel, eluting with0%-15% ethyl acetate-hexane to obtain the title compound (3.55 g, 78%).¹H NMR (300 MHz, DMSO-d₆) δ ppm 7.83 (m, 1H), 7.79 (m, 1H), 3.92 (s,4H), 2.41-2.07 (m, 4H), 1.91-1.63 (m, 4H). MS (DCI) m/z 244 (M+H)⁺.

Example 27C 4-fluoro-4-(thiazol-2-yl)cyclohexanone

To a solution of the product of Example 27B (3.55 g, 14.59 mmol) indioxane (40 mL) was added 1M HCl (100 mL). The reaction mixture wasstirred overnight at ambient temperature, quenched with 10M NaOH (10 mL)and extracted with three portions of 1:1 ethyl acetate-hexanes. Thecombined organic layers were concentrated. The resulting residue waschromatographed on silica gel eluting with 0%-20% ethyl acetate-hexaneto obtain the title compound (2.15 g, 74%). ¹H NMR (300 MHz, DMSO-d₆) δppm 7.82-7.95 (m, 2H), 2.61-2.72 (m, 6H), 2.24-2.42 (m, 2H).

MS (DCI) m/z 200 (M+H)⁺.

Example 27D 4-fluoro-4-(thiazol-2-yl)cyclohex-1-enyltrifluoromethanesulfonate

To a −78° C. solution of the product of Example 27C (2.15 g, 10.79 mmol)and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(3.85 g, 10.79 mmol) in tetrahydrofuran (30 mL) was added lithiumbis(trimethylsilyl)amide (1M in tetrahydrofuran, 13.95 mL, 13.95 mmol)over 5 minutes. The reaction mixture was allowed to warm to ambienttemperature and stirred overnight. The reaction mixture was then dilutedwith ethyl acetate and hexane, and washed with 1N sodium hydroxide andbrine. The organic layer was concentrated, and the residuechromatographed on silica gel eluting with 0%-20% ethyl acetate-hexaneto obtain the title compound (2.54 g, 71%). ¹H NMR (300 MHz, DMSO-d₆) δppm 7.85-7.95 (m, 2H), 5.90-6.08 (m, 1H), 2.94-3.21 (m, 1H), 2.74-2.95(m, 1H), 2.58-2.74 (m, 1H), 2.17-2.50 (m, 3H). MS (DCI) m/z 332 (M+H)⁺.

Example 27E4-fluoro-4-(1,3-thiazol-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting 4-(trifluoromethylsulfonyl)anilinefor 4-(trifluoromethyl)aniline, and substituting the product of Example27D for the product of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.52(s, 1H), 7.99-8.23 (m, 4H), 7.82-7.96 (m, 2H), 6.79 (br s, 1H),2.99-3.26 (m, 1H), 2.92 (m, 1H), 2.73 (m, 1H), 2.20-2.43 (m, 2H),2.04-2.21 (m, 1H). MS (DCI) m/z 435 (M+H)⁺. Calcd for C₁₇H₁₄F₄N₂O₃S₂: C,47.00; H, 3.25; N, 6.45. Found: C, 47.26; H, 3.25; N, 6.33.

Example 28(4R)-4-(3-chloropyridin-2-yl)-4-fluoro-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide

The title compound was isolated from the chiral separation of Example 3by Preparative Supercritical Fluid Chromatography (SFC) (Chiralpak AD-H3 cm ID×25 cm column, 30% ethanol in SFC CO₂ at 150 bar, 40 g/min flowrate, 40° C. column temp) as the first eluting enantiomer. ¹H NMR (300MHz, CDCl₃) δ ppm 8.46 (d, J=4.7, 1H), 8.00 (d, J=8.9, 2H), 7.89 (d,J=8.9, 2H), 7.82-7.74 (m, 2H), 7.28-7.22 (m, 1H), 6.78 (s, 1H),3.38-3.15 (m, 1H), 3.10-2.91 (m, 1H), 2.79-2.55 (m, 3H), 2.49-2.23 (m,1H); MS (ESI) m/e 463 (M+H)⁺; [α]_(D): +13.9° (c 1.0, MeOH); Calcd forC₁₉H₁₅ClF₄N₂O₃S: C, 49.30; H, 3.27; N, 6.05. Found: C, 49.12; H, 3.19;N, 5.99.

Example 29(4S)-4-(3-chloropyridin-2-yl)-4-fluoro-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide

The title compound was isolated from the chiral separation of Example 3by Prep SFC (Chiralpak AD-H 3 cm ID×25 cm column, 30% ethanol in SFC CO₂at 150 bar, 40 g/min flow rate, 40° C. column temp) as the secondeluting enantiomer. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.46 (ddd, J=4.5, 1.2,0.7, 1H), 8.00 (d, J=8.9, 2H), 7.89 (d, J=8.9, 2H), 7.82-7.74 (m, 2H),7.29-7.22 (m, 1H), 6.78 (s, 1H), 3.39-3.15 (m, 1H), 3.10-2.91 (m, 1H),2.80-2.54 (m, 3H), 2.48-2.23 (m, 1H); MS (ESI) m/e 463 (M+H)⁺; [α]_(D):−12.2° (c 1.0, MeOH); Calcd for C₁₉H₁₅ClF₄N₂O₃S: C, 49.30; H, 3.27; N,6.05. Found: C, 49.17; H, 3.06; N, 6.02.

Example 30N-{4-[(difluoromethyl)sulfonyl]phenyl}-4-fluoro-4-(3-fluoropyridin-2-yl)cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting 4-(difluoromethylsulfonyl)anilinefor 4-(trifluoromethyl)aniline, and substituting the product of Example15D for the product of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 10.37(s, 1H), 8.45 (d, J=4.6, 1H), 8.08 (d, J=9.0, 2H), 7.91 (d, J=9.0, 2H),7.83 (ddd, J=1.3, 8.4, 11.8, 1H), 7.56 (app dt, J=4.2, 8.4, 1H), 7.23(t, J=52.3, 1H(CF₂H)), 6.80 (br s, 1H), 3.28-3.04 (m, 1H), 2.98-2.67 (m,1H), 2.61-2.35 (m, 3H), 2.35-2.03 (m, 1H). MS (DCI) m/z 429 (M+H)⁺.Calcd for C₁₉H₁₆F₄N₂O₃S: C, 53.27; H, 3.76; N, 6.54. Found: C, 53.00; H,3.61; N, 6.36.

Example 314-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1 E, except for substituting 4-aminophenylsulfur pentafluoride(Aldrich) for 4-(trifluoromethyl)aniline. ¹H NMR (300 MHz, DMSO-d₆) δppm 10.18 (s, 1H), 8.61-8.50 (m, 1H), 8.03 (dd, J=1.4, 8.1, 1H),7.96-7.77 (m, 4H), 7.55-7.41 (m, 1H), 6.76 (s, 1H), 3.06 (ddd, J=11.5,24.1, 47.8, 2H), 2.58-2.41 (m, 3H), 2.38-2.10 (m, 1H). MS (DCI) m/z 457(M+H)⁺. Calcd for C₁₈H₁₅ClF₆N₂OS: C, 47.32; H, 3.31; N, 6.13. Found: C,47.27; H, 3.25; N, 6.01.

Example 324-(3-chloropyridin-2-yl)-4-fluoro-6-methyl-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamideExample 32A 4-(tert-butyldimethylsilyloxy)-2-methylcyclohexanone

To a 5.0 L round bottom flask containing4-(tert-butyldimethylsilyloxy)cyclohexanone (7.03 g, 30.8 mmol)(Aldrich) was added THF (100 mL) and the reaction was cooled to −78° C.To the reaction mixture was added lithium bis(trimethylsilyl)amide (33.9ml, 33.9 mmol) (Aldrich) and the reaction mixture was stirred for 30minutes followed by the addition of iodomethane (2.309 ml, 36.9 mmol).The reaction mixture was stirred for 30 minutes at −78° C. and 2 hoursat room temperature, quenched with saturated NH₄Cl, extracted with EtOAc(200 mL), dried (NaSO₄), filtered, and concentrated in vacuo. Theresidue was purified on SiO₂ and eluted with 0-20% ethyl acetate/hexaneto give a white solid (6.40 g) in 86% yield. ¹H NMR (300 MHz, CDCl₃) δppm 4.19-4.07 (m, 1H), 2.98-2.72 (m, 1H), 2.50-1.99 (m, 2H), 1.91-1.64(m, 2H), 1.62-1.44 (m, 1H), 1.15 (dt, J=4.4, 6.8, 1H), 1.07-0.99 (m,3H), 0.95-0.85 (m, 9H), 0.11 (d, J=1.6, 6H). MS (DCI⁺) M/Z 243.

Example 32Btert-Butyldimethyl(6-methyl-1,4-dioxaspiro[4,5]decan-8-yloxy)silane

To a 200 mL round bottom flask containing Example 32A (6.25 g, 25.8mmol), ethylene glycol (1.725 mL, 30.9 mmol) and p-toluenesulfonic acidmonohydrate (1.471 g, 7.73 mmol) (Aldrich) was added benzene (80 mL) andthe reaction mixture was heated at reflux for 18 hr. The reactionmixture was quenched with sat NH₄OH, extracted with EtOAc (200 mL),dried (NaSO₄), filtered, and concentrated in vacuo. The residue waspurified on SiO₂ and eluted with hexane ethyl acetate 0-20% to afford acolorless oil (6.57 g) in 89% yield. ¹H NMR (300 MHz, CDCl₃) δ ppm4.23-4.04 (m, 5H), 3.07-2.92 (m, 1H), 2.53-2.04 (m, 2H), 1.94-1.72 (m,2H), 1.60-1.44 (m, 1H), 1.18 (dt, J=4.4, 6.8, 1H), 1.10-1.00 (m, 3H),0.90-0.80 (m, 9H), 0.14 (d, J=1.6, 6H). MS (DCI+) M/Z 287 (M+H)+.

Example 32C 6-Methyl-1,4-dioxaspiro[4.5]decan-8-ol

To a 200 mL round bottom flask containing Example 32B (3.95 g, 13.79mmol) was added TBAF (27.6 ml, 27.6 mmol) (Aldrich) and the reactionmixture was stirred at room temperature for 3 hours. The mixture waspoured into saturated sodium bicarbonate, extracted with ethyl acetate(200 mL), dried over sodium sulfate, filtered, and concentrated invacuo. The residue was purified on SiO₂ and eluted with hexane/ethylacetate 0 to 40% over 60 minutes to afford a colorless oil (1.50 g) in63% yield. ¹H NMR (300 MHz, CDCl₃) δ ppm 4.00-3.86 (m, 4H), 3.69 (dt,J=5.4, 14.8, 1H), 2.25-1.19 (m, 7H), 0.94-0.81 (m, 3H). MS (DCI⁺) M/Z173 (M+H)⁺.

Example 32D 6-Methyl-1,4-dioxaspiro[4.5]decan-8-one

To a 200 mL round bottom flask containing the product of Example 32C(1.50 g, 8.71 mmol) and DMP (4.06 g, 9.58 mmol) (Aldrich) was addedmethylene chloride (100 mL) and the reaction mixture was stirred for 1hr at room temperature. The reaction mixture was quenched with saturatedNaHCO₃ and extracted with EtOAc (200 mL), dried (NaSO₄), filtered, andconcentrated in vacuo. The residue was purified on SiO₂ withhexane/ethylacetate 0-20% to afford a colorless oil (1.12 g) in 76%yield. ¹H NMR (300 MHz, CDCl₃) δ ppm 4.20-3.95 (m, 4H), 2.63-1.97 (m,6H), 1.94-1.74 (m, 1H), 1.04-0.83 (m, 3H). MS (DCI⁺) M/Z 171 (M+H)⁺.

Example 32E8-(3-Chloropyridin-2-yl)-6-methyl-1,4-dioxaspiro[4.5]decan-8-ol

To a 200 mL round bottom flask containing diethyl ether (40 mL) wasadded n-butyllithium (IM) (3.41 ml, 8.52 mmol) (Aldrich) followed byaddition of 2-bromo-3-chloropyridine (1.639 g, 8.52 mmol) (Aldrich) andthe reaction was stirred for 1 hr at −65° C. Example 32D (1.45 g, 8.52mmol) was added to the reaction in 20 mL of diethyl ether and stirredfor 30 minutes. The reaction mixture was slowly warmed to roomtemperature and stirred for 2 hours, quenched with saturated NaHCO₃ andextracted with EtOAc (200 mL), dried (NaSO₄), filtered, and concentratedin vacuo. The material was purified on SiO₂ and eluted with hexane/ethylacetate (20%) to give a colorless oil (1.295 g) in 53.4% yield. ¹H NMR(300 MHz, CDCl₃) δ ppm 8.52-8.34 (m, 1H), 7.77-7.60 (m, 1H), 7.20 (ddd,J=4.6, 6.1, 7.9, 1H), 4.04-3.85 (m, 4H), 2.99-2.79 (m, 2H), 2.56-2.33(m, 1H), 2.24-1.99 (m, 2H), 1.33-1.12 (m, 2H), 1.03-0.81 (d, 3H). MS(DCI⁺) M/Z 284 (M+H)⁺.

Example 32F3-Chloro-2-(8-fluoro-6-methyl-1,4-dioxaspiro[4.5]decan-8-yl)pyridine

A solution of Example 32E (1.30 g, 4.58 mmol) in dichloromethane (100mL) was cooled to −78° C., treated with diethylaminosulfur trifluoride(0.730 ml, 5.96 mmol) (Aldrich), and the reaction mixture was stirred at−78° C. for 2 hours. After 2 hours the reaction was partially completeand the mixture was allowed to stir for 2 additional hours. The reactionmixture was poured into dichloromethane (200 mL) and washed withsaturated Na₂CO₃, dried over Na₂SO₄, and concentrated in vacuo. Thematerial was purified on SiO₂ and eluted with hexane/ethyl acetate (20%)to give a white solid (0.625 g) in 48% yield. ¹H NMR (300 MHz, CDCl₃) δppm 8.46 (dd, J=1.6, 4.7, 1H), 7.67 (dt, J=1.2C, 8.0, 1H), 7.17-7.09 (m,1H), 4.17-3.92 (m, 4H), 2.72 (ddd, J=5.4, 10.7, 19.5, 3H), 2.57-2.50 (m,1H), 2.25-2.15 (m, 1H), 2.06-1.94 (m, 1H), 1.83 (dd, J=6.0, 14.1, 1H),1.08 (dd, J=6.9, 20.9, 3H). MS (DCI⁺) M/Z 286 (M+H)⁺.

Example 32G 4-(3-Chloropyridin-2-yl)-4-fluoro-2-methylcyclohexanone

To a 200 mL round bottom flask was added Example 32F (0.612 g, 2.142mmol) in 10 mL of 1,4-dioxane. To the reaction was added 3N HCl (10 mL)and the reaction was stirred at room temperature for 5 hours. Thereaction mixture was poured into H₂O, neutralized with Na₂CO₃, extractedwith ethyl acetate (200 mL), dried over Na₂SO₄, and concentrated invacuo. The material was purified on SiO₂ and eluted with hexane/ethylacetate (20%) to give a white solid (0.43 g) in 84% yield. ¹H NMR (300MHz, CDCl₃) δ ppm 8.45-8.38 (m, 1H), 7.74 (dt, J=6.7, 13.6, 1H),7.30-7.24 (m, 1H), 3.13-2.85 (m, 3H), 2.82-2.71 (m, 2H), 2.63-2.12 (m,2H), 1.14 (dt, J=3.3, 10.1, 3H). MS (DCI+) M/Z 242 (M+H)⁺.

Example 32H 4-(3-Chloropyridin-2-yl)-4-fluoro-6-methylcyclohex-1-enyltrifluoromethanesulfonate

In a 200 mL round bottomed flask was added1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(0.727 g, 2.034 mmol) (Aldrich) in THF (20 mL) and Example 32G (0.447 g,1.849 mmol). The reaction was cooled to −78° C. and LiHMDS (0.95 mL, 1Min THF) (Aldrich) was added and the reaction was stirred at −78° C. for1 hr. The reaction was warmed to room temperature and stirred for 1hour. The mixture was concentrated in vacuo and taken up in ethylacetate (200 mL). The organic portion was washed with saturated sodiumbicarbonate (50 mL), brine (50 mL), dried (sodium sulfate), filtered andconcentrated in vacuo. The crude material was purified on SiO₂ andeluted with hexane/ethyl acetate 4/1 to obtain the title compound as awhite solid (0.58 g) in 84% yield. ¹H NMR (300 MHz, CDCl₃) δ ppm8.50-8.37 (m, 1H), 7.75 (dd, J=1.5, 8.0, 1H), 7.22 (dd, J=4.0, 8.4, 1H),5.81-5.68 (m, 1H), 3.28-2.89 (m, 2H), 2.79-2.61 (m, 1H), 2.25-2.01 (m,2H), 1.29 (s, 3H). MS (DCI+) M/Z 374 (M+H)+.

Example 32I4-(3-chloropyridin-2-yl)-4-fluoro-6-methyl-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide

To a 200 mL round bottom flask containing DMF (20 mL) was addedpalladium acetate (II) (0.014 g, 0.064 mmol) (Strem), Example 32H (0.120g, 0.321 mmol), triethylamine (0.090 ml, 0.642 mmol) (Aldrich) and4-(trifluoromethyl)aniline (0.067 g, 0.417 mmol) (Aldrich). The reactionmixture was subjected to CO(g) and the reaction was stirred at roomtemperature for 2 hours. The reaction was concentrated to ¼ volume andpoured into 150 mL of ethyl acetate, washed with saturated bicarbonate,dried (sodium sulfate), filtered and concentrated in vacuo. The crudemixture was purified on SiO₂ (Analogix® SF65-200 g 35 micron silica) andeluted with CH₂Cl₂/hexane (1/1) with a 0 to 20% ethyl acetate gradientover 60 minutes with a 120 minute hold. Example 32I was obtained as awhite solid in a 54% yield (72 mg). ¹H NMR (300 MHz, DMSO-d₆) δ ppm10.28 (s, 1H), 8.57 (d, J=4.5, 1H), 8.02 (dd, J=1.4, 8.1, 2H), 7.91 (s,1H), 7.68 (d, J=8.7, 2H), 7.49 (dd, J=4.2, 7.9, 1H), 6.41 (s, 1H),3.18-2.94 (m, 2H), 2.77-2.47 (m, 2H), 2.09-1.64 (m, 1H), 1.07 (d, J=6.8,3H). MS (DCI+) M/Z 413 (M+H)+.

Example 334-(3-chloropyridin-2-yl)-4-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamideExample 33A3-(tert-Butyldimethylsilyloxy)-6-(3-chloropyridin-2-yl)-N,N-dimethyl-6-(trifluoromethyl)cyclohex-2-enamine

A solution of Example 26A (612 mg, 2.95 mmol) and(E)-3-(tert-butyldimethylsilyloxy)-N,N-dimethylbuta-1,3-dien-1-amine(966 mg, 4.25 mmol) in toluene (2.5 mL) was heated on a microwave at 60°C. for 30 minutes, and then 70° C. for 30 minutes. Purified by silicagel chromatography (AnaLogix® SF25-40G; 50 micron silica; elution with0-50% ethyl acetate in hexane at 30 mL/min) to provide the titlecompound (787 mg, 1.81 mmol, 61.4% yield) as a light yellow oil. MS(DCI/NH₃) m/e 435 (M+H)⁺.

Example 33B 4-(3-Chloropyridin-2-yl)-4-(trifluoromethyl)cyclohex-2-enone

To a solution of Example 33A (787 mg, 1.81 mmol) in tetrahydrofuran (22mL) was added 1N hydrochloric acid (4.0 mL, 4.0 mmol), and stirredovernight at ambient temperature. The reaction mixture was quenched withsodium bicarbonate solution (100 mL), extracted twice with ethyl acetate(100 mL), washed with brine, dried (Na₂SO₄) and concentrated. Theresidue was purified by silica gel chromatography (AnaLogix® SF15-24G;50 micron silica; eluted with 0-40% ethyl acetate in hexane at 20mL/min) to provide the title compound (449 mg, 1.63 mmol, 90% yield) asa white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.58 (dd, J=4.5, 1.6, 1H),7.77 (d, J=1.7, 1H), 7.74 (dd, J=2.5, 1.9, 1H), 7.29 (dd, J=8.1, 4.5,1H), 6.15 (d, J=10.4, 1H), 3.62-3.52 (m, 1H), 2.57-2.46 (m, 1H), 2.41(dd, J=12.7, 4.0, 1H), 2.32-2.18 (m, 1H); MS (DCI/NH₃) m/e 276 (M+H)⁺.

Example 33C 4-(3-Chloropyridin-2-yl)-4-(trifluoromethyl)cyclohexanone

Example 33B (539 mg, 1.96 mmol) was added to a mixture oftetrahydrofuran (12 mL) and wet 5% platinum-on-carbon (112.7 mg) in aParr shaker. The glass reactor was sealed and flushed with argon, andthen it was pressurized with hydrogen (30 psi). The mixture was shakenat ambient temperature for 20 hours, filtered, rinsed with methanol, andconcentrated. The residue was purified by silica gel chromatography(AnaLogix® SF15-24G; 50 micron silica, eluted with 0-40% ethyl acetatein hexane at 20 mL/min) to provide the title compound (318 mg, 1.15mmol, 58.6% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.63(dd, J=4.4, 1.6, 1H), 7.79 (dd, J=8.2, 1.6, 1H), 7.30 (dd, J=8.0, 4.4,1H), 3.65-3.50 (m, 2H), 2.53-2.38 (m, 2H), 2.31-2.13 (m, 4H); MS(DCI/NH₃) m/e 278 (M+H)⁺.

Example 33D 4-(3-Chloropyridin-2-yl)-4-(trifluoromethyl)cyclohex-1-enyltrifluoromethanesulfonate

A solution of Example 33C (304 mg, 1.095 mmol) andN-phenyltrifluoromethane-sulfonamide (430 mg, 1.20 mmol) intetrahydrofuran (10 mL) was chilled to −75° C., treated with 1M lithiumbis(trimethylsilyl)amide (1.3 mL, 1.3 mmol) in tetrahydrofuran, stirredat −75° C. for 1.5 hours, removed cooling bath, and stirred overnight atambient temperature. The reaction mixture was quenched with 1N sodiumhydroxide (100 mL), extracted twice with ethyl acetate (100 mL), washedwith brine, dried (Na₂SO₄), and concentrated. The reaction mixture waspurified by silica gel chromatography (AnaLogix® SF15-24G; 50 micronsilica; eluted with 0-20% ethyl acetate in hexane at 20 mL/min) toprovide the title compound (287 mg, 0.700 mmol, 64% yield) as acolorless oil. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.52 (dd, J=4.5, 1.6, 1H),7.73 (dd, J=8.0, 1.5, 1H), 7.24 (dd, J=8.0, 4.4, 1H), 5.78 (d, J=6.7,1H), 3.97-3.85 (m, 1H), 3.53-3.45 (m, 1H), 2.64-2.53 (m, 1H), 2.51-2.36(m, 1H), 2.28-2.12 (m, 2H); MS (DCI/NH₃) m/e 410 (M+H)⁺.

Example 33E4-(3-Chloropyridin-2-yl)-4-(trifluoromethyl)-N-(4-(trifluoromethyl)phenyl)cyclohex-1-enecarboxamide

A solution of Example 33D (283 mg, 0.691 mmol),4-(trifluoromethyl)aniline (167 mg, 1.036 mmol), and triethylamine(0.193 mL, 1.38 mmol) in dimethylformamide (3 mL) was added topalladium(II) acetate (3.88 mg, 0.017 mmol) and2-dicyclohexylphospino-2′-(dimethylamino)-biphenyl (13.59 mg, 0.035mmol) in a pressure bottle under argon. The mixture was pressurized withcarbon monoxide (60 psi), and stirred for 3.5 hours at ambienttemperature, diluted with ethyl acetate (100 mL), washed with water (100mL) and brine, dried (Na₂SO₄), and concentrated to a brown oil. Themixture was purified by silica gel chromatography twice [(1) AnaLogix®SF15-24G; 50 micron silica; eluted with 0-25% ethyl acetate in hexane at20 mL/min; (2) AnaLogix® SF15-24G; 50 micron silica; eluted withdichloromethane at 20 mL/min)] to provide the title compound (149 mg,0.332 mmol, 48.1% yield) as a white solid. ¹H NMR (300 MHz, CDCl₃) δ ppm8.51 (dd, J=4.4, 1.6, 1H), 7.72 (dd, J=8.1, 1.6, 1H), 7.61 (d, J=8.9,2H), 7.54 (d, J=8.8, 2H), 7.37 (s, 1H), 7.22 (dd, J=8.1, 4.5, 1H), 6.74(d, J=4.9, 1H), 4.07-3.95 (m, 1H), 3.56-3.49 (m, 1H), 2.67-2.56 (m, 2H),2.18-2.08 (m, 2H); MS (ESI) m/e 449 (M+H)⁺; Calcd for C₂₀H₁₅ClF₆N₂O: C,53.53; H, 3.37; N, 6.24. Found: C, 53.45; H, 3.10; N, 5.99.

Example 344-(3-chloropyridin-2-yl)-4-fluoro-N-(4-isopropylphenyl)cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting 4-isopropylaniline for4-(trifluoromethyl)aniline. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.48-8.44 (m,1H), 7.76 (dd, J=8.1, 1.5, 1H), 7.47 (d, J=8.6, 2H), 7.41 (s, 1H), 7.24(dd, J=3.6, 0.6, 1H), 7.20 (d, J=8.6, 2H), 6.68 (s, 1H), 3.32-3.08 (m,1H), 3.06-2.81 (m, 2H), 2.78-2.51 (m, 3H), 2.48-2.24 (m, 1H), 1.24 (d,J=6.9, 6H); MS (ESI) m/e 373 (M+H)⁺; Calc'd for C₂₁H₂₂ClFN₂O: C, 67.65;H, 5.95; N, 7.51. Found: C, 67.42; H, 6.04; N, 7.42.

Example 354-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(2,2,2-trifluoro-1-methylethyl)phenyl]cyclohex-1-ene-1-carboxamideExample 35A tert-Butyl 4-(3,3,3-trifluoroprop-1-en-2-yl)phenylcarbamate

To a mixture of tert-butyl 4-bromophenylcarbamate (1.67 g, 6.14 mmol),potassium carbonate (3.38 g, 24.46 mmol), andtetrakis(triphenylphosphine)palladium (365 mg, 0.316 mmol), was added4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane(1.64 g, 7.39 mmol), and degassed 1,2-dimethoxyethane (40 mL) and water(20 mL). The mixture for refluxed for 2 hours, cooled to ambienttemperature, added more of4,4,6-trimethyl-2-(3,3,3-trifluoroprop-1-en-2-yl)-1,3,2-dioxaborinane(475 mg, 2.14 mmol) and tetrakis(triphenylphosphine)palladium-(189 mg,0.164 mmol), and refluxed for 5 hours. The reaction mixture was cooledto room temperature, filtered, diluted with water (200 mL), extractedtwice with ethyl acetate (200 mL), washed with brine, dried (Na₂SO₄) andconcentrated to an orange oil. The residue was purified by silica gelchromatography (AnaLogix® SF25-40G; 50 micron silica; eluted with 0-15%ethyl acetate in hexane at 30 mL/min) to provide the title compound(1.223 g, 4.26 mmol, 69.4% yield) as a yellow solid. ¹H NMR (300 MHz,DMSO-d₆) δ ppm 9.53 (s, 1H), 7.52 (d, J=8.8, 2H), 7.40 (d, J=8.4, 2H),6.03-5.99 (m, 1H), 5.97-5.94 (m, 1H), 1.48 (s, 9H); MS (DCI/NH₃) m/e 305(M+NH₄)⁺.

Example 35B tert-Butyl 4-(1,1,1-trifluoropropan-2-yl)phenylcarbamate

Example 35A (1.223 g, 4.26 mmol) was added to a mixture oftetrahydrofuran (10 mL), methanol (20 mL), and 5% palladium-on-carbon(0.24 g) in a Parr shaker. The glass reactor was sealed and flushed withargon, and then pressurized with hydrogen (40 psi). The mixture wasshaken at ambient temperature for 6 hours. The palladium was filteredoff and rinsed with methanol. The filtrate was concentrated and purifiedby silica gel chromatography (AnaLogix® SF15-24G; 50 micron silica;eluted with 0-20% ethyl acetate in hexane at 20 mL/min) to provide thetitle compound (1.129 g, 3.90 mmol, 92% yield) as a pink solid. ¹H NMR(300 MHz, DMSO-d₆) δ ppm 9.36 (s, 1H), 7.44 (d, J=8.6, 2H), 7.25 (d,J=8.7, 2H), 3.76-3.57 (m, 1H), 1.47 (s, 9H), 1.40 (d, J=7.2, 3H); MS(DCI/NH₃) m/e 307 (M+NH₄)⁺.

Example 35C 4-(1,1,1-Trifluoropropan-2-yl)aniline

To a solution of Example 35B (1.059 g, 3.66 mmol) in dichloromethane (10mL) was added trifluoroacetic acid (1.0 mL, 12.98 mmol), and stirred atambient temperature for 3.5 hours. The reaction mixture wasconcentrated, treated with 3N sodium hydroxide (50 mL), extracted twicewith diethyl ether (50 mL), washed with brine, dried (Na₂SO₄), andconcentrated. The reaction mixture was purified the oil by silica gelchromatography (AnaLogix® SF15-24G; 50 micron silica; eluted with 0-30%ethyl acetate in hexane at 20 mL/min) to provide the title compound (635mg, 3.36 mmol, 92% yield) as a liquid. ¹H NMR (300 MHz, DMSO-d₆) δ ppm6.99 (d, J=8.4, 2H), 6.53 (d, J=8.5, 2H), 5.08 (s, 2H), 3.55-3.41 (m,1H), 1.35 (d, J=7.2, 3H); MS (DCI/NH₃) m/e 190 (M+H)⁺.

Example 35D4-(3-Chloropyridin-2-yl)-4-fluoro-N-(4-(1,1,1-trifluoropropan-2-yl)phenyl)cyclohex-1-enecarboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting Example 35C for4-(trifluoromethyl)aniline. ¹H NMR (300 MHz, CDCl₃) δ ppm 8.47-8.44 (m,1H), 7.76 (dd, J=8.1, 1.3, 1H), 7.56 (d, J=8.6, 2H), 7.47 (s, 1H), 7.29(d, J=8.6, 2H), 7.25-7.21 (m, 1H), 6.72-6.67 (m, 1H), 3.47-3.34 (m, 1H),3.33-3.10 (m, 1H), 3.06-2.89 (m, 1H), 2.72-2.52 (m, 3H), 2.47-2.24 (m,1H), 1.50 (d, J=7.3, 3H); MS (ESI) m/e 427 (M+H)⁺; Calcd forC₂₁H₁₉ClF₄N₂O: C, 59.09; H, 4.49; N, 6.56. Found: C, 59.35; H, 4.49; N,6.51.

Example 366-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}bicyclo[4.1.0]hept-3-ene-3-carboxamideExample 36A8-(3-(trifluoromethyl)pyridine-2-yl)-1,4-dioxaspiro[4.5]decan-8-ol

The title compound was prepared using a similar procedure as describedin Example 1A, substituting 2-bromo-3-(trifluoromethyl)pyridine (4.61 g,20.4 mmol) for 2-bromo-3-chloropyridine. Yield 3.5 g, 57%

Example 36B2-(1,4-Dioxaspiro[4,5]dec-7-en-8-yl)-3-(trifluoromethy)pyridine

To a −78° C. solution of Example 36A (1.2 g, 3.96 mmol) in CH₂Cl₂ (25mL) was added DAST (0.97 g, 0.76 mL, 5.75 mmol) and the reaction mixturewas allowed to warm to ambient temperature. The mixture was quenchedwith water, diluted with EtOAc, and washed with water. Organic layer wasseparated, concentrated and chromatographed on silica gel (EtOAc-hexane,0%-30%) to obtain the title compound (0.9 g, 80%). ¹H NMR (300 MHz,DMSO-d₆) δ ppm 8.78 (m, 1H), 8.17 (dd, J=1.6, 8.2, 1H), 7.51 (m, 1H),5.56 (m, 1H), 3.92 (s, 4H), 2.35 (m, 3H), 1.94 (dd, J=9.1, 16.3, 1H),1.80 (t, J=6.5, 2H). MS (DCI) m/z 286 (M+H)⁺.

Example 36C2-(Spirobicyclo[4.10]heptane-3,2′-[1,3]dioxolane]-6-yl)-3-(trifluoromethyl)pyridine

To a −78° C. solution of diethylzinc (3.86 mL, 3.86 mmol) (1M solutionin hexane) in CH₂Cl₂ (4 mL) was added a solution of diiodomethane (0.62mL, 7.71 mmol) in CH₂Cl₂ (2 mL). After the reaction mixture was stirredat −15° C. for 30 min, a solution of trifluoroacetic acid (0.30 mL, 3.86mmol) in CH₂Cl₂ (2 mL) was added. After an additional 30 min ofstirring, a solution of Example 36B (0.55 g, 1.93 mmol) in CH₂Cl₂ (2 mL)was added and reaction mixture stirred at 0° C. for 1 h. The reactionmixture was allowed to warm to ambient temperature stirred at ambienttemperature for 16 h, and refluxed for 3 h, cooled to ambienttemperature, quenched with water, and extracted with EtOAc. Organicphase was separated, concentrated in vacuo and the residuechromatographed on silica gel (EtOAc-Hexanes, 20-100%) to obtain thetitle compound (0.10 g, 17%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.75 (dd,J=0.9, 4.8, 1H), 8.10 (m, 1H), 7.48 (m, 1H), 3.84 (m, 4H), 2.26-1.00 (m,9H). MS (DCI) m/z 300 (M+H)⁺.

Example 36D6-(3-trifluoromethyl)pyridine-2-yl)bicyclo[4.1.0]heptan-3-one

To a solution of Example 36C (0.12 g, 0.40 mmol) in dioxane (2.5 mL) wasadded 3M aq. HCl (2.5 mL). The reaction mixture was allowed to warm toambient temperature for 2 h before quenching with 3M aq. NaOH. Reactionmixture was diluted with EtOAc and washed twice with water. Organicphase was separated, concentrated in vacuo, and the residuechromatographed on silica gel (EtOAc-CH₂Cl₂, 10-100%) to obtain thetitle compound (0.06 g, 59%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.79 (dd,J=0.9, 4.8, 1H), 8.16 (m, 1H), 7.53 (m, 1H), 2.78 (m, 1H), 2.35-2.08 (m,5H), 1.67-1.53 (m, 1H), 1.23-1.07 (m, 2H). MS (DCI) m/z 256 (M+H)⁺.

Example 36E6-(3-trifluoromethyl)pyridine-2-yl)bicyclo[4.1.0]hept-2-en-3-yltrifluoromethanesulfonate

The title compound was prepared using a similar procedure as describedin Example 1D, substituting Example 36D (0.065 g, 0.255 mmol) forExample 1C. Yield 0.03 g, 30%. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.79 (m,1H), 8.17 (m, 1H), 7.55 (m, 1H), 5.84 (dt, J=2.8, 5.4, 1H), 2.82 (m,3H), 1.69 (m, 1H), 1.27 (m, 2H), 0.88 (t, J=5.6, 1H). MS (DCI) m/z 388(M+H)⁺.

Example 36F6-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}bicyclo[4.1.0]hept-3-ene-3-carboxamide

The title compound was prepared using a similar procedure as describedin Example 1E, substituting Example 36E (0.03 g, 0.077 mmol) for Example1D and substituting 4-(trifluoromethylsulfonyl)aniline for4-(trifluoromethyl)aniline. Yield 0.023 g, 61%. ¹H NMR (300 MHz, DMSO) δppm 10.46 (s, 1H), 8.81 (d, J=3.8, 1H), 8.26-7.96 (m, 5H), 7.55 (m, 1H),6.68 (s, 1H), 2.75-0.76 (m, 7H). MS (DCI) m/z 491 (M+H)⁺.

Example 374-(3-chloropyridin-2-yl)-4-fluoro-6-methyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 32I, except for substituting 4-(trifluoromethylsulfonyl)anilinefor 4-(trifluoromethyl)aniline. The product was obtained in 64% yield.¹H NMR (300 MHz, CDCl₃) δ ppm 8.52-8.43 (m, 1H), 8.01 (d, J=8.8, 1H),7.95-7.87 (m, 2H), 7.83-7.66 (m, 2H), 7.30-7.19 (m, 1H), 6.54-6.41 (m,1H), 3.09 (ddd, J=19.3, 37.0, 59.8, 3H), 2.77-2.59 (m, 1H), 2.05 (ddd,J=10.4, 14.1, 36.7, 1H), 1.16 (d, J=6.9, 3H). MS (DCI+) M/Z 477 (M+H)⁺.

Example 384-(3-chloropyridin-2-yl)-4-methyl-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamideExample 38A 2-(3-chloropyridin-2-yl)propanenitrile

To a −78° C. solution of diisopropylamine (3.04 g, 4.28 mL, 30 mmol) wasadded n-butyl lithium (13.2 mL, 2.5M in hexane, 33 mmol). The reactionmixture was stirred for 20 minutes at −78° C., followed by the additionof propionitrile (1.65 g, 2.15 mL, 30 mmol). The reaction mixture wasstirred for an additional 50 minutes, followed by the slow addition of2-bromo-3-chloropyridine (1.92 g, 10 mmol) in THF (10 mL). The reactionwas then allowed to warm to ambient temperature and stirred overnight.The reaction mixture was quenched with water and extracted with twoportions of diethyl ether. The combined organic phases were washed withbrine, concentrated, and the residue chromatographed on silica geleluting with 30% ethyl acetate-hexane to obtain the title compound (1.52g, 91%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.59 (dd, J=1.5, 4.7, 1H), 8.02(dd, J=1.5, 8.1, 1H), 7.48 (dd, J=4.7, 8.1, 1H), 4.73 (q, J=7.1, 1H),1.59 (d, J=7.1, 3H). MS (DCI) m/z 167 (M+H)⁺.

Example 38B Ethyl 2-(3-chloropyridin-2-yl)propanoate

The product of Example 38A (1.15 g, 6.9 mmol) was dissolved in absoluteethanol (14 mL) and cooled to 0° C. Concentrated sulfuric acid (13.54 g,7.36 mL, 138 mmol) was added, and the reaction mixture was allowed towarm to ambient temperature. The reaction was then heated at reflux for2 hours, cooled, and poured onto ice. The mixture was neutralized withsaturated aqueous sodium bicarbonate, and extracted with two portions ofethyl acetate. The organic layers were separated and concentrated togive the title compound (1.34 g, 91%) which was used without furtherpurification. ¹H NMR (300 MHz, DMSO-d₆) δ ppm8.49 (dd, J=1.5, 4.7, 1H),7.93 (dd, J=1.5, 8.1, 1H), 7.36 (dd, J=4.7, 8.1, 1H), 4.29 (q, J=7.1,1H), 4.07 (q, J=7.1, 2H), 1.42 (d, J=7.1, 3H), 1.11 (t, J=7.1, 3H). MS(DCI) m/z 214 (M+H)⁺.

Example 38C 2-(3-chloropyridin-2-yl)propan-1-ol

To a −15° C. solution of the product of Example 38B (1.34 g, 6.27 mmol)in tetrahydrofuran (25 mL) was added lithium aluminum hydride (0.238 g,6.27 mmol). The reaction mixture was kept between −5° C. and −15° C. for1 hour and then quenched by the addition of solid sodium sulfatedecahydrate. The quenched reaction mixture was filtered through a pad ofcelite with ethyl acetate and the filtrate concentrated. The residue waschromatographed on silica gel with 35% ethyl acetate-hexane to give thetitle compound (0.90 g, 84%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm8.49 (dd,J=1.5, 4.6, 1H), 7.85 (dd, J=1.6, 8.1, 1H), 7.26 (dd, J=4.6, 8.1, 1H),4.70-4.55 (m, 1H), 3.82-3.62 (m, 1H), 3.59-3.39 (m, 2H), 1.16 (d, J=6.5,3H). MS (DCI) m/z 172 (M+H)⁺.

Example 38D 2-(3-chloropyridin-2-yl)propanal

To a −78° C. solution of dimethylsulfoxide (4.04 g, 3.67 mL, 51.7 mmol)in methylene chloride (25 mL) was added a solution of oxalyl chloride(3.28 g, 2.26 mL, 25.9 mmol) in methylene chloride (5 mL) over twominutes. The reaction mixture was stirred for 15 minutes, and then asolution of the product of Example 38C (0.74 g, 4.31 mmol) in methylenechloride (25 mL) was added over 8 minutes. The reaction was allowed towarm to ambient temperature and quenched with water. The quenchedreaction mixture was extracted with methylene chloride, and the organiclayer washed with brine and concentrated. The residue waschromatographed on silica gel eluting with 25% ethyl acetate-hexane togive the title compound (0.71 g, 97%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm9.73 (s, 1H), 8.53 (dd, J=1.5, 4.7, 1H), 8.00 (dd, J=1.4, 8.1, 1H), 7.40(dd, J=4.7, 8.1, 1H), 4.28 (q, J=7.0, 1H), 1.34 (d, J=7.0, 3H). MS (DCI)m/z 170 (M+H)⁺.

Example 38E 4-(3-chloropyridin-2-yl)-4-methylcyclohex-2-enone

To a 0° C. solution of the product of Example 38D (0.71 g, 4.19 mmol) indiethyl ether (10 mL) was added a solution of potassium hydroxide (3M inmethanol, 0.56 mL, 1.68 mmol), followed by methyl vinyl ketone (0.47 g,0.55 mL, 6.70 mmol). The reaction was allowed to warm to ambienttemperature and stirred overnight. The reaction mixture was diluted withdiethyl ether, and washed with water and brine. The organic layer wasconcentrated, and the residue was chromatographed on silica gel elutingwith 25% ethyl acetate-hexane to give the title compound (0.20 g, 22%).¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.53 (dd, J=1.5, 4.6, 1H), 7.92 (dd,J=1.5, 8.0, 1H), 7.45-7.26 (m, 2H), 5.92 (d, J=10.2, 1H), 2.82-2.67 (m,1H), 2.64-2.52 (m, 1H), 2.31 (ddd, J=4.8, 7.2, 17.3, 1H), 2.12-2.00 (m,1H). MS (DCI) m/z 222 (M+H)⁺.

Example 38F 4-(3-chloropyridin-2-yl)-4-methylcyclohexanone

A solution of the product of Example 38E (0.225 g, 1.015 mmol) in DMFwas added to 5% Pt—C, wet (225 mg, 1.153 mmol) in a 50 ml pressurebottle. The mixture was pressurized with hydrogen (40 psi), stirred for16 hours at ambient temperature, filtered to remove catalyst, andconcentrated. The residue was chromatographed on silica gel eluting with30% ethyl acetate-hexanes to give the title compound (90 mg, 40%). ¹HNMR (300 MHz, DMSO-d₆) δ ppm 8.55 (dd, J=1.5, 4.6, 1H), 7.91 (dd, J=1.5,8.0, 1H), 7.36 (dd, J=4.6, 8.0, 1H), 2.96-2.77 (m, 2H), 2.26 (dd, J=5.4,8.1, 4H), 2.03-1.84 (m, 2H), 1.46 (s, 3H). MS (DCI) m/z 224 (M+H)⁺.

Example 38G 4-(3-chloropyridin-2-yl)-4-methylcyclohex-1-enyltrifluoromethanesulfonate

To a −78° C. solution of the product of Example 38F (90 mg, 0.40 mmol)and1,1,1-trifluoro-N-phenyl-N-(trifluoromethylsulfonyl)methanesulfonamide(144 mg, 0.40 mmol) in tetrahydrofuran (2.5 mL) was added lithiumbis(trimethylsilyl)amide (1M in tetrahydrofuran, 0.48 mL, 0.48 mmol).The reaction mixture was allowed to warm to ambient temperature andstirred overnight. The reaction mixture was then diluted with ethylacetate and hexane, and washed with 1N sodium hydroxide and brine. Theorganic layer was concentrated, and the residue chromatographed onsilica gel eluting with 8% ethyl acetate-hexane to obtain the titlecompound (117 mg, 82%). ¹H NMR (300 MHz, DMSO-d₆) δ ppm 8.46 (dd, J=1.6,4.5, 1H), 7.88 (dd, J=1.6, 8.0, 1H), 7.33 (dd, J=4.5, 8.0, 1H),5.99-5.86 (m, 1H), 3.21-3.07 (m, 1H), 2.78-2.57 (m, 1H), 2.43-2.28 (m,2H), 2.17-1.90 (m, 2H), 1.43 (s, 3H). MS (DCI) m/z 356 (M+H)⁺.

Example 38H4-(3-chloropyridin-2-yl)-4-methyl-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting the product of Example 38G for theproduct of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.86 (s, 1H),8.46 (d, J=3.2, 1H), 7.99-7.79 (m, 3H), 7.64 (d, J=8.6, 2H), 7.31 (dd,J=4.5, 8.0, 1H), 6.85 (br s, 1H), 3.45-3.09 (m, 2H), 2.65-2.21 (m, 2H),2.15-1.83 (m, 2H), 1.44 (s, 3H). MS (DCI) m/z 395 (M+H)⁺. Calcd forC₂₀H₁₈ClF₃N₂O.0.2H₂O: C, 60.29; H, 4.65; N, 7.03. Found: C, 60.10; H,4.48; N, 6.89.

Example 39N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-4-methylcyclohex-1-ene-1-carboxamide

The title compound was prepared using the procedure as described inExample 1E, except for substituting 4-tert-butylaniline for4-(trifluoromethyl)aniline, and substituting the product of Example 38Gfor the product of Example 1D. ¹H NMR (300 MHz, DMSO-d₆) δ ppm 9.41 (s,1H), 8.47 (dd, J=1.5, 4.5, 1H), 7.87 (dd, J=1.5, 8.0, 1H), 7.55 (d,J=8.7, 2H), 7.41-7.20 (m, 3H), 6.76 (br s, 1H), 3.42-3.08 (m, 2H),2.62-2.22 (m, 2H), 2.15-1.83 (m, 2H), 1.43 (s, 3H), 1.25 (s, 9H). MS(DCI) m/z 383 (M+H)⁺. Calcd for C₂₃H₂₇ClN₂O.0.2H₂O: C, 71.47; H, 7.14;N, 7.25. Found: C, 71.50; H, 6.89; N, 6.96.

It is understood that the foregoing detailed description andaccompanying examples are merely illustrative and are not to be taken aslimitations upon the scope of the invention, which is defined solely bythe appended claims and their equivalents. Various changes andmodifications to the disclosed embodiments will be apparent to thoseskilled in the art. Such changes and modifications, including withoutlimitation those relating to the chemical structures, substituents,derivatives, intermediates, syntheses, formulations and/or methods ofuse of the invention, may be made without departing from the spirit andscope thereof.

1. A compound of formula (I)

or a pharmaceutically acceptable salt, prodrug, salt of a prodrug, or a combination thereof, wherein R¹ is phenyl or a monocyclic heteroaryl, each of which is optionally substituted with 1, 2, 3, 4, or 5 substituents as represented by R⁶ groups; R² is halogen, alkyl, haloalkyl, —CN, —O(alkyl), —O(haloalkyl), —OH, —NH₂, —N(H)(alkyl), or —N(alkyl)₂; or R² and the adjacent carbon atom, together with the carbon atom to which R² is attached, form a 3-6 membered monocyclic cycloalkyl ring that is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the group consisting of alkyl, hydroxyalkyl, alkoxyalkyl, haloalkoxyalkyl, haloalkyl, arylalkyl, aryl, aminoalkyl, amino, and halogen, wherein the aryl and the aryl moiety of the arylalkyl are each independently unsubstituted or substituted with 1, 2, 3, 4, or 5 substituents selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, OH, O(alkyl), O(haloalkyl), amino, and haloalkyl; R³ is hydrogen or C₁₋₆ alkyl; R⁴ is aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle, wherein each R⁴ is optionally substituted with 1, 2, 3, 4, 5, or 6 substituents as represented by R⁷ groups; R⁵ represents an optional substituent on the cycloalkene ring, and is haloalkyl, halogen, —OH, —NO₂, NH₂, N(H)(alkyl), N(alkyl)₂, alkyl, alkenyl, alkynyl, or -G¹; X is O, S, or N(R^(z)) wherein R^(z) is hydrogen, alkyl, or CN; m is 0, 1, or 2; n is 0 or 1; R⁷, at each occurrence, is independently alkyl, alkenyl, alkynyl, oxo, —NO₂, —CN, halogen, -G², —OR^(a), —OC(O)R^(a), —SR^(a), —SF₅, —S(O)R^(b), —S(O)₂R^(b), —S(O)₂N(R^(a))(R^(c)), —N(R^(a))(R^(c)), —N(R^(c))C(O)R^(a), —N(R^(c))S(O)₂R^(b), —N(R^(c))C(O)N(R^(a))(R^(c)), —N(R^(c))S(O)₂N(R^(a))(R^(c)), —C(O)R^(a), —C(O)O(R^(a)), —C(O)N(R^(a))(R^(c)), haloalkyl, —(CR^(j)R^(k))_(p)—CN, —(CR^(j)R^(k))_(p)—OR^(a), —(CR^(j)R^(k))_(p)—OC(O)R^(a), —(CR^(j)R^(k))_(p)—SR^(a), —(CR^(j)R^(k))_(p)—S(O)R^(b), —(CR^(j)R^(k))_(p)—S(O)₂R^(b), —(CR^(j)R^(k))_(p)N(R^(a))(R^(c)), —(CR^(j)R^(k))_(p)—N(R^(c))C(O)R^(a), —(CR^(j)R^(k))_(p)—N(R^(c))S(O)₂R^(b), —(CR^(j)R^(k))_(p)—N(R^(c))C(O)N(R^(a))(R^(c)), —(CR^(j)R^(k))_(p)—N(R^(c))S(O)₂N(R^(a))(R^(c)), —(CR^(j)R^(k))_(p)—C(O)R^(a), —(CR^(j)R^(k))_(p)—C(O)O(R^(a)), —(CR^(j)R^(k))_(p)—C(O)N(R^(a))(R^(c)), or —(CR^(j)R^(k))_(p)-G²; R^(a), at each occurrence, is independently hydrogen, alkyl, haloalkyl, -G², or —(CR^(u)R^(v))_(w)-G²; R^(b), at each occurrence, is independently alkyl, haloalkyl, -G², or —(CR^(u)R^(v))_(w)-G²; G¹ and G², are each independently aryl, heteroaryl, cycloalkyl, cycloalkenyl, or heterocycle; each of which is independently unsubstituted or substituted with 1, 2, 3, 4, 5, or 6 substituents as represented by R⁸ groups; R⁶, at each occurrence, is independently alkyl, alkenyl, alkynyl, —NO₂, —CN, halogen, —OR^(d), —OC(O)R^(d), —SR^(d), —S(O)R^(e), —S(O)₂R^(e), —S(O)₂N(R^(d))(R^(f)), —N(R^(d))(R^(f)), —N(R^(f))C(O)R^(d), —N(R^(f))S(O)₂R^(e), —N(R^(f))C(O)N(R^(d))(R^(f)), —N(R^(f))S(O)₂N(R^(d))(R^(f)), —C(O)R^(d), —C(O)O(R^(d)), —C(O)N(R^(d))(R^(f)), haloalkyl, —(CR^(s)R^(t))_(q)—CN, —(CR^(s)R^(t))_(q)—OR^(a), —(CR^(s)R^(t))_(q)—OC(O)R^(d)—(CR^(s)R^(t))_(q)—SR^(d), —(CR^(s)R^(t))_(q)—S(O)R^(e), —(CR^(s)R^(t))_(q)—S(O)₂R^(e), —(CR^(s)R^(t))_(q)—N(R^(d))(R^(f)), —(CR^(s)R^(t))_(q)—N(R^(f))C(O)R^(d), —(CR^(s)R^(t))_(q)—N(R^(f))S(O)₂R^(e), —(CR^(s)R^(t))_(q)—N(R^(f))C(O)N(R^(d))(R^(f)), —(CR^(s)R^(t))_(q)—N(R^(f))S(O)₂N(R^(d))(R^(f)), —(CR^(s)R^(t))_(q)—C(O)R^(d), —(CR^(s)R^(t))_(q)—C(O)O(R^(d)), or —(CR^(s)R^(t))_(q)—C(O)N(R^(d))(R^(f)); R⁸, at each occurrence, is independently alkyl, alkenyl, alkynyl, oxo, —NO₂, —CN, halogen, —OR^(d), —OC(O)R^(d), —SR^(d), —S(O)R^(e), —S(O)₂R^(e), —S(O)₂N(R^(d))(R^(f)), —N(R^(d))(R^(f)), —N(R^(f))C(O)R^(d), —N(R^(f))S(O)₂R^(e), —N(R^(f))C(O)N(R^(d))(R^(f)), —N(R^(f))S(O)₂N(R^(d))(R^(f)), —C(O)R^(d), —C(O)O(R^(d)), —C(O)N(R^(d))(R^(f)), haloalkyl, —(CR^(s)R^(t))_(q)—CN, —(CR^(s)R^(t))_(q)—OR^(a), —(CR^(s)R^(t))_(q)—OC(O)R^(d), —(CR^(s)R^(t))_(q)—SR^(d), —(CR^(s)R^(t))_(q)—S(O)R^(e), —(CR^(s)W)_(q)—S(O)₂R^(e), —(CR^(s)R^(t))_(q)—N(R^(d))(R^(f)), —(CR^(s)R^(t))_(q)—N(R^(f))C(O)R^(d), —(CR^(s)R^(t))_(q)—N(R^(f))S(O)₂R^(e), —(CR^(s)R^(t))_(q)—N(R^(f))C(O)N(R^(d))(R^(f)), —(CR^(s)R^(t))_(q)—N(R^(f))S(O)₂N(R^(d))(R^(f)), —(CR^(s)R^(t))_(q)—C(O)R^(d), —(CR^(s)R^(t))_(q)—C(O)O(R^(d)), or —(CR^(s)R^(t))_(q)—C(O)N(R^(d))(R^(f)); R^(c)C, R^(d) and R^(f), at each occurrence, are each independently hydrogen, alkyl, or haloalkyl; R^(e), at each occurrence, is independently alkyl or haloalkyl; R^(j), R^(k), R^(s), R^(t), R^(u), and R^(v), at each occurrence, are each independently hydrogen, halogen, alkyl, or haloalkyl; and p, q, and w, at each occurrence, are each independently 1, 2, 3, or
 4. 2. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R² is halogen or alkyl.
 3. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein m is 1 and X is O.
 4. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R¹ is optionally substituted phenyl.
 5. The compound according to claim 3 or a pharmaceutically acceptable salt thereof, wherein R¹ is optionally substituted monocyclic heteroaryl.
 6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the monocyclic heteroaryl is pyridinyl.
 7. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R⁴ is optionally substituted heteroaryl.
 8. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R⁴ is optionally substituted phenyl.
 9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R² is halogen or alkyl.
 10. The compound according to claim 1 having formula (III), or a pharmaceutically acceptable salt thereof

wherein R², R⁵, R⁶, R⁷, and n are as defined in formula (I).
 11. The compound of claim 10 or a pharmaceutically acceptable salt thereof wherein R² is halogen or alkyl.
 12. The compound of claim 13 or a pharmaceutically acceptable salt thereof wherein n is
 0. 13. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of 4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide; N-(4-chlorophenyl)-4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-ene-1-carboxamide; 4-(3-chloropyridin-2-yl)-4-fluoro-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide; N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-ene-1-carboxamide; 4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethoxy)phenyl]cyclohex-1-ene-1-carboxamide; 4-(3-chloropyridin-2-yl)-N-[4-(1-cyano-1-methylethyl)phenyl]-4-fluorocyclohex-1-ene-1-carboxamide; 4-(3-chloropyridin-2-yl)-4-methoxy-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide; 4-(3-chloropyridin-2-yl)-4-methoxy-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide; 4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide; 4-fluoro-4-(3-methylpyridin-2-yl)-N-[4-(trifluoromethoxy)phenyl]cyclohex-1-ene-1-carboxamide; 4-fluoro-4-(3-methylpyridin-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide; N-(4-chlorophenyl)-4-fluoro-4-(3-methylpyridin-2-yl)cyclohex-1-ene-1-carboxamide; N-(4-tert-butylphenyl)-4-fluoro-4-(3-methylpyridin-2-yl)cyclohex-1-ene-1-carboxamide; 4-fluoro-4-(3-fluoropyridin-2-yl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide; N-(4-tert-butylphenyl)-4-fluoro-4-(3-fluoropyridin-2-yl)cyclohex-1-ene-1-carboxamide; 4-fluoro-4-(3-fluoropyridin-2-yl)-N-[5-(trifluoromethyl)pyridin-2-yl]cyclohex-1-ene-1-carboxamide; 4-fluoro-4-(3-fluoropyridin-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide; 4-fluoro-4-(3-fluoropyridin-2-yl)-N-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]cyclohex-1-ene-1-carboxamide; 4-fluoro-4-(1,3-thiazol-2-yl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide; 4-fluoro-4-(1,3-thiazol-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide; (4R)—N-(4-chlorophenyl)-4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-ene-1-carboxamide; (4S)—N-(4-chlorophenyl)-4-(3-chloropyridin-2-yl)-4-fluorocyclohex-1-ene-1-carboxamide; (4R)-4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide; (4S)-4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide; 4-[3-(dimethylamino)pyridin-2-yl]-4-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide; 4-fluoro-4-(1,3-thiazol-2-yl)-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide; (4R)-4-(3-chloropyridin-2-yl)-4-fluoro-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide; (4S)-4-(3-chloropyridin-2-yl)-4-fluoro-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide; N-{4-[(difluoromethyl)sulfonyl]phenyl}-4-fluoro-4-(3-fluoropyridin-2-yl)cyclohex-1-ene-1-carboxamide; 4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(pentafluoro-λ⁶-sulfanyl)phenyl]cyclohex-1-ene-1-carboxamide; 4-(3-chloropyridin-2-yl)-4-fluoro-6-methyl-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide; 4-(3-chloropyridin-2-yl)-4-(trifluoromethyl)-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide; 4-(3-chloropyridin-2-yl)-4-fluoro-N-(4-isopropylphenyl)cyclohex-1-ene-1-carboxamide; 4-(3-chloropyridin-2-yl)-4-fluoro-N-[4-(2,2,2-trifluoro-1-methylethyl)phenyl]cyclohex-1-ene-1-carboxamide; 6-[3-(trifluoromethyl)pyridin-2-yl]-N-{4-[(trifluoromethyl)sulfonyl]phenyl}bicyclo[4.1.0]hept-3-ene-3-carboxamide; 4-(3-chloropyridin-2-yl)-4-fluoro-6-methyl-N-{4-[(trifluoromethyl)sulfonyl]phenyl}cyclohex-1-ene-1-carboxamide; 4-(3-chloropyridin-2-yl)-4-methyl-N-[4-(trifluoromethyl)phenyl]cyclohex-1-ene-1-carboxamide; and N-(4-tert-butylphenyl)-4-(3-chloropyridin-2-yl)-4-methylcyclohex-1-ene-1-carboxamide.
 14. A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
 15. The pharmaceutical composition of claim 14 further comprises acetaminophen or one or more nonsteroidal anti-inflammatory drug, or a combination thereof.
 16. The pharmaceutical composition of claim 15 wherein the nonsteroidal anti-inflammatory drug is ibuprofen.
 17. A method for treating a disorder wherein the disorder is ameliorated by inhibiting transient receptor potential vanilloid-1 (TRPV1) in a host mammal in need of such treatment comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
 18. A method for treating pain in a mammal in need of such treatment, comprising administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
 19. The method of claim 18 further comprising the step of co-administering with acetaminophen, or with one or more nonsteroidal anti-inflammatory drug, or a combination thereof
 20. The method of claim 19 wherein the nonsteroidal anti-inflammatory drug is ibuprofen.
 21. A method for treating acute cerebral ischemia, pain, chronic pain, neuropathic pain, nociceptive pain, allodynia, inflammatory pain, post herpetic neuralgia, neuropathies, neuralgia, diabetic neuropathy, HIV-related neuropathy, nerve injury, rheumatoid arthritic pain, osteoarthritic pain, burns, back pain, visceral pain, cancer pain, dental pain, headache, migraine, carpal tunnel syndrome, fibromyalgia, neuritis, sciatica, pelvic hypersensitivity, pelvic pain, menstrual pain, bladder disease, micturition disorder, renal colic; inflammation, neurodegenerative disease, pulmonary disease, gastrointestinal disease, ischemia, emesis, or obesity, said method comprising the step of administering a therapeutically effective amount of a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, to a subject in need thereof. 